U.S. patent number 5,245,034 [Application Number 07/856,178] was granted by the patent office on 1993-09-14 for compound having vessel smooth muscle relaxation activity.
This patent grant is currently assigned to Kiroyoshi Hidaka. Invention is credited to Masatoshi Hagiwara, Hiroyoshi Hidaka, Takashi Inaba, Tsutomu Inoue, Tomohiko Ishikawa, Tadashi Morita, Kenji Naitoh, Osamu Sakuma, Tadashi Toshioka, Isao Umezawa, Masayuki Yuasa.
United States Patent |
5,245,034 |
Hidaka , et al. |
September 14, 1993 |
Compound having vessel smooth muscle relaxation activity
Abstract
Novel quinoline sulfonamino derivatives having a vessel smooth
muscle relaxation activity as well as a platelet agglutination
inhibitory activity and inhibitory activity to protein kinase A,
myosin light chain kinase, proteinkinase C, and calmodulindependent
proteinkinase II, but having little action or cardio function; a
process for the production of the derivatives, and a pharmaceutical
composition containing the derivative.
Inventors: |
Hidaka; Hiroyoshi (Nagoya,
JP), Ishikawa; Tomohiko (Nagoya, JP),
Hagiwara; Masatoshi (Nagoya, JP), Inoue; Tsutomu
(Funabashi, JP), Naitoh; Kenji (Akishima,
JP), Sakuma; Osamu (Tama, JP), Yuasa;
Masayuki (Akishima, JP), Morita; Tadashi
(Kashiwa, JP), Toshioka; Tadashi (Urayasu,
JP), Umezawa; Isao (Tokyo, JP), Inaba;
Takashi (Higashimurayama, JP) |
Assignee: |
Hidaka; Kiroyoshi (Aichi,
JP)
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Family
ID: |
27551358 |
Appl.
No.: |
07/856,178 |
Filed: |
March 23, 1992 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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758808 |
Sep 12, 1991 |
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453623 |
Dec 20, 1989 |
5081246 |
Jan 14, 1992 |
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Foreign Application Priority Data
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Dec 26, 1988 [JP] |
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63-325910 |
Mar 30, 1989 [JP] |
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1-76419 |
Apr 10, 1989 [JP] |
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1-87868 |
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Current U.S.
Class: |
546/149; 540/575;
544/121; 544/130; 544/159; 544/295; 544/362; 544/363; 544/370;
544/389; 544/391; 544/394; 546/140; 546/206; 546/242; 546/338;
548/561; 549/491; 549/75 |
Current CPC
Class: |
C07C
311/16 (20130101); C07D 217/02 (20130101); C07D
217/10 (20130101); C07D 491/10 (20130101); C07D
401/14 (20130101); C07D 405/12 (20130101); C07D
409/12 (20130101); C07D 401/12 (20130101) |
Current International
Class: |
C07C
311/00 (20060101); C07C 311/16 (20060101); C07D
405/12 (20060101); C07D 405/00 (20060101); C07D
409/12 (20060101); C07D 217/10 (20060101); C07D
409/00 (20060101); C07D 217/00 (20060101); C07D
217/02 (20060101); C07D 401/12 (20060101); C07D
401/00 (20060101); C07D 401/14 (20060101); C07D
491/00 (20060101); C07D 491/10 (20060101); C07D
401/12 () |
Field of
Search: |
;544/363,128
;546/149 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0061673 |
|
Jan 1982 |
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EP |
|
0097630 |
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Jan 1984 |
|
EP |
|
0109023 |
|
May 1984 |
|
EP |
|
0187371 |
|
Jul 1986 |
|
EP |
|
0287696 |
|
Oct 1988 |
|
EP |
|
0330065 |
|
Aug 1989 |
|
EP |
|
0330910 |
|
Sep 1989 |
|
EP |
|
2845941 |
|
May 1979 |
|
DE |
|
6081168 |
|
May 1955 |
|
JP |
|
52-100439 |
|
Aug 1977 |
|
JP |
|
52-111550 |
|
Sep 1977 |
|
JP |
|
60-81168 |
|
May 1985 |
|
JP |
|
61-126026 |
|
Jun 1986 |
|
JP |
|
61-271221 |
|
Dec 1986 |
|
JP |
|
61-293914 |
|
Dec 1986 |
|
JP |
|
61-293914 |
|
Dec 1986 |
|
JP |
|
63-22757 |
|
Mar 1987 |
|
JP |
|
62-87581 |
|
Apr 1987 |
|
JP |
|
62-103066 |
|
May 1987 |
|
JP |
|
63-2980 |
|
Jan 1988 |
|
JP |
|
63-17870 |
|
Jan 1988 |
|
JP |
|
63-211267 |
|
Sep 1988 |
|
JP |
|
6211198 |
|
May 1989 |
|
JP |
|
2007663 |
|
Nov 1989 |
|
GB |
|
Other References
Wagner et al., Chemical Abstract vol. 96 p. 757 96:104709m (1982).
.
Claeson, et al., Chemical Abstract vol. 100 p. 570 100: 156982r
(1984). .
Chemical Abstracts 212215 u (1985). .
Chemical Abstracts 11096 k (1982). .
Chemical Abstracts 37665 v (1987). .
Chemical Abstracts, vol. 88(3):22461v, Jan. 16, 1978. .
Chemical Abstract 99:32993m. .
Chemical Abstract 98:103351t. .
J. Starzebecher et al. Pharmazie (1984) H.6 411-413. .
Struzebecher, J. et al., Die Pharmazie vol. 42(2) 1987 114, 115,
118. .
Wagner et al. Chem. Abs. vol. 91 91:108231u (1979). .
Markwardt, et al. Chemical Abstract vol. 92 p. 236 92:176396x
(1980)..
|
Primary Examiner: Dentz; Bernard
Assistant Examiner: Turnipseed; James H.
Attorney, Agent or Firm: Ladas & Parry
Parent Case Text
This is a divisional of copending application Ser. No. 07/758,808
filed Sep. 12, 1991 which is a divisional of application Ser. No.
07/453,623 filed Dec. 20, 1989 (now U.S. Pat. No. 5,081,246 issued
Jan. 14, 1992).
Claims
We claim:
1. A compound represented by the formula (I): ##STR29## wherein
R.sub.1 and R.sub.3 each represents a hydrogen atom, formyl or
halogen-substituted phenylpropargyl; or R.sub.1 and R.sub.3 each
represents a group of the formula: R--(CH.sub.2)m'-- wherein R is a
hydrogen atom, hydroxy, methoxy, cyano, amino, methylamino,
dimethylamino, carboxy, carbamoyl, methoxycarbonyl, piperidyl,
piperidino, morpholino, morpholinocarbonyl, piperazino,
4'-methylpiperazino, pyridyl, 5'-methylimidazol-4'-yl, phenyl,
hydroxy-substituted phenyl or phenyl substituted by 1 to 3
substituents of methoxy group; and m' represents an integer of 0 to
4; or R.sub.1 and R.sub.3 together form a ethylene ring;
R.sub.4 is a hydrogen atom or methyl;
R.sub.5 is selected from the group consisting of a hydrogen atom; a
halogen atom, a lower alkyl, methoxy, methoxycarbonyl, carboxy,
hydroxy, hydroxymethyl, cyano, carbamoyl, acetylamino,
dimethylamino, nitro, methylthio methylsulfinyl, methylsulfonyl,
trifluoromethyl or methoxyethoxymethoxy;
R.sub.6 is a hydrogen atom, a halogen atom or methoxy; or R.sub.6
and R.sub.5 together form a methylenedioxy group or a phenylene
ring;
R.sub.7 is a hydrogen atom or methoxy;
X is a vinylene group or an ethynylene group;
m is an integer of 1 to 3; and
W represents ethylene, propylene, pyridylene, phenylene or
methoxycarbonyl-substituted phenylene; and quarternary ammonium
salts, or salts of the compound of the formula (I).
2. A compound according to claim 1 which is
N-anisyl-N-[2-(4-chlorocinnamylamino)
ethyl]-5-isoquinolinesulfonamide.
Description
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to compounds having a vessel smooth
muscle relaxation activity, a process for the production thereof,
and to the use thereof.
2. Description of the Related Art
Quinoline compounds having a vessel smooth muscle relaxation
activity are described in, for example, Japanese Unexamined Patent
Publication (KOKAI) Nos. 60-81168, 61-126026, 61-271221, 61-293914,
62-103066, and 63-211267; and U.S. Pat. Nos. 4,456,757, 4,525,589,
4,560,755, 4,634,770, 4,678,783, 4,709,032, and 4,798,897.
Among the compounds described in the above references, some have a
satisfactory smooth muscle relaxation activity, but have problems
with relation to toxicity, organ-specificity, and safety.
SUMMARY OF THE INVENTION
Accordingly, the objects of the present invention are to provide
novel compounds having a satisfactory smooth muscle relaxation
activity, and a low toxicity, high organ-specificity, and high
safety.
More particularly, the present invention provides a compound
represented by the formula (I): ##STR1## wherein Y represents N,
H.sub.3 C--N or CH;
R.sub.1 represents a hydrogen atom, an optionally substituted lower
alkyl group, a formyl group, a halophenylpropargyl group, an
optionally substituted aralkyl group or optionally substituted
phenyl; and
(1) R.sub.2 represents a group represented by the formula (II):
##STR2## wherein R.sub.3 represents a hydrogen atom, an optionally
substituted lower alkyl group, a formyl group, a
halophenylpropargyl group, an optionally substituted aralkyl group
or optionally substituted phenyl; or R.sub.1 and R.sub.3 together
form a lower alkylene group;
R.sub.4 represents a hydrogen atom or a lower alkyl group;
R.sub.5 represents a hydrogen atom, a halogen atom, a nitro group,
a lower alkyl group, an optionally substitute hydroxyl group, an
optionally substituted N-substituted amino group, an optionally
substituted carboxy group, a polyfluoro-lower alkyl group, a cyano
group, a hydroxymethyl group, a methylthio group, methyl sulfinyl
group or methylsulfonyl group;
R.sub.6 represents a hydrogen atom, a halogen atom or a lower
alkoxy group; or
R.sub.5 and R.sub.6 together form a lower alkylenedioxy group;
R.sub.7 represents a hydrogen atom or a lower alkoxy group;
X represents a vinylene group or an ethynylene group;
Ar represents a phenyl group, a naphthyl group or a heterocyclyl
group;
m represents an integer of 1 to 3; and
W represents a lower alkylene group, an optionally substituted
phenylene group or an optionally substituted phenylene-lower
alkylene group; or
(2) R.sub.2 represents a group represented by the formula (III):
##STR3## wherein R.sub.10 represents a hydrogen atom, a nitro
group, an optionally substituted amino group, an optionally
substituted hydroxyl group, a lower alkyl group, or a halogen atom;
or R.sub.1 and R.sub.10 together form a lower alkylene group;
R.sub.11 represents a hydrogen atom, a hydroxyl group or a lower
alkoxy group;
R.sub.12 and R.sub.13 each represent a hydrogen atom, or together
represent .dbd.O;
Ar has the same meaning as defined under the formula (II);
n represents an integer of 1 to 3; and
A represents the group >CR.sub.14 R.sub.15 or >NR.sub.14 ;
wherein R.sub.14 represents a hydrogen atom, an optionally
substituted hydroxy group, an optionally substituted phenyl group,
an acyl group, a substituted carbonyl group, an optionally
substituted alkoxycarbonyl, a substituted carbamoyl, an optionally
substituted amino group, an arylsulfonyl group, an aralkylsulfonyl
group, an aralkyl group, or a heterocyclyl group; and
R.sub.15 represents a hydrogen atom or a lower alkoxy group, or
R.sub.15 and R.sub.14 together represent an alkylenedioxy group or
.dbd.O; and
quaternary ammonium salts of the compound of the formula (I), and
nontoxic salts of the compound of the formula (I).
The present invention above provides a process for the production
of a compound represented by the formula (I) wherein R.sub.2
represents a group represented by the formula (II), comprising the
steps of
(1) reacting a compound represented by the formula (IV): ##STR4##
wherein Y, W, R.sub.1 and R.sub.3 have the same meanings as defined
above, with a compound represented by the formula (V): ##STR5##
wherein B represents --CH.sub.2 Hal or --CO--R.sub.4, and other
symbols have the same meanings as defined in claim 1; and
optionally
(2) reducing a compound produced in the spet (1), and/or
optionally
(3) alkylating or formylating a compound produced in the step (1)
or (2).
The present invention moreover provides a process for the
production of a compound represented by the formula (I) wherein
R.sub.2 represents a group represented by the formula (II),
comprising the steps of:
(1) reacting a compound represented by the formula (VI): ##STR6##
with a compound represented by the formula (VII): ##STR7## or a
reactive derivative thereof or a salt thereof, wherein all the
symbols in the formula (VI) and (VII) have the same meanings as
defined above, and optionally,
(2) alkylating a compound produced in the step (1).
The present invention still further provides a process for the
production of a compound represented by the formula (I), according
to claim 1, wherein R.sub.2 represents a group represented by the
formula (III), comprising the steps of:
(1) reacting a compound represented by the formula (VIII). ##STR8##
with a compound represented by the formula (VII): ##STR9## or a
reactive derivative thereof or a salt thereof, wherein all the
symbols in the formulae (VII) and (VIII) have the some meanings as
defined above;
and optionally carrying out one or more than one of the following
steps (2) to (8),
(2) hydrolysis to form a free hydroxyl group or an amino group;
(3) deprotection of a protecting group for a hydroxyl or amino
group;
(4) acylation or substituted-alkoxycarbonylation of a hydroxyl
group or an amino group;
(5) alkylation of a hydroxyl group or an amino group;
(6) amination or hydroxylation of a carbonyl group;
(7) reduction of a nitro group to an amino group; and
(8) carbonylation of an acetal.
The present invention also provides a pharmaceutical composition
comprising a compound described above.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the definition of the present invention, the optionally
substituted lower alkyl includes an unsubstituted lower alkyl and a
substituted lower alkyl. "Lower alkyl" means an alkyl containing up
to seven carbon atoms, preferably up to four carbon atoms. The
unsubstituted lower alkyl include straight chain lower alkyl and
branched chain lower alkyl and are, for example, methyl, ethyl,
n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl
and heptyl.
In the definition of R.sub.1 and R.sub.3, the substituted lower
alkyls include an optionally substituted amino lower alkyl, such as
2-amino ethyl and 3-amino propyl, N,N-dimethyl amino propyl,
4-piperidyl lower alkyl such as 4-piperidyl propyl, a morpholino
lower alkyl such as morpholinoethyl, and piperidino lower alkyl
such as piperidinoethyl. The halophenylpropargyl includes fluoro-
chloro-, brom- and iode-phenylproparyls, and is preferably
p-chlorophenylpropargyl. The optionally substituted aralkyls
include unsubstituted aralkyl, for example, a phenyl lower alkyl
such as benzyl and phenylethyl, and a substituted phenyl-lower
alkyl such as p-methoxybenzyl. The optionally substituted phenyl
includes a substituted phenyl such as 3,4-dimethoxy phenyl. The
alkylene group formed by R.sub.1 and R.sub.3 is, for example, a
methylene, ethylene, or propylene group.
The lower alkyl as R.sub.4 is as defined above.
The halogen as R.sub.5 is floro, chloro, bromo or iodo; preferably
chloro.
The lower alkyl as R.sub.5 is as defined above.
The optionally substituted hydroxy as R.sub.5 includes a hydroxyl
group, and a substituted hydroxyl group, for example, a lower
alkoxy such as methoxy, ethoxy or propoxy.
The optionally N-substituted amino as R.sub.5 is an amino, or a
lower alkyl amino such as dimethylamino.
The optionally substituted carboxy as R.sub.5 includes a carboxyl
group, per se., and a substituted carboxy, for example, a lower
alkoxy carbonyl such as methoxy carbonyl, ethoxycarbonyl, and
propoxycarbonyl.
The polyfluoro-lower alkyl as R.sub.5 is, for example,
trifluoromethyl.
The halogen as R.sub.6 is as defined above for R.sub.5.
The lower alkoxy as R.sub.6 is as defined above for R.sub.5.
The lower alkylenedioxy formed by R.sub.5 and R.sub.6 is, for
example, methylenedioxy, 1,2-ethylenedioxy, 1,3-dipropylenedioxy,
1,2-dipropylenedioxy, or the like, preferably
1,2-ethylenedioxy.
The lower alkoxy as R.sub.7 is as defined above for R.sub.5.
The lower alkylene group as W is, for example, a methylene group,
ethylene group, 1,3-propylene group, or 1,4-butylene group.
The phenylene group as W is, for example, a 1,2-phenylene group or
1,3-phenylene. The phenylene lower alkylene group as W is, for
example, a 1,2-phenylene- or 1,3-phenylene-lower alkylene group
such as 1,2-phenylene-ethylene or a 1,3-phenylene-ethylene group.
The optional substituent for the phenylene moiety is, for example,
a lower alkoxy carbonyl such as methoxy carbonyl.
The heterocyclyl group as Ar is, for example, a pyridyl such as
2-pyridyl, 3-pyridyl or 4-pyridyl, a pyridyl such as 2 pyridyl,
3-pyridyl or 4-pyridyl, a pyrrolyl such as 2-pyrrolyl or
3-pyrrolyl, a thionyl such as 2-thionyl a 3-thionyl, or a furyl
such as 2-furyl or 3-furyl.
The optionally substituted amino as R.sub.10 includes free amino
and substituted amino. In the substituted amino, the substituents
are exemplified by a lower alkyl such as methyl, ethyl, propyl or
other lower alkyl as defined above, and substituted sulfo such as
isoquinoline sulfo, naphtharenesulfo, methanesulfo, toluenesulfo.
Accordingly, the substituted amino is, for example, isoquinoline
sulfonamide, N-lower alkyl isoquinolinesulfonamide such as
N-methyl-sulfonamide, naphtharenesulfonamide, N-lower alkyl
naphtharenesulfonamide such as N-methylnaphtharenesulfonamide,
methansulfonamide, N-lower alkyl methansulfonamide, N-methyl
methansulfonamide, toluenesulfonamide, or N-lower alkyl
methansulfonamide such as N-methyl methanesulfonamide. The
substituted amino further is phtharimide.
The substituted hydroxy group as R.sub.10 includes ester, ether and
protected hydroxy. The ester is, for example, a substituted
sulfonyloxy such as isoquinolinesulfonyloxy, toluenesulfonyloxy or
naphtharenesulfonyloxy, or a lower alkanoyloxy such as acetoxy,
propionyloxy or butanoyloxy. The ether is, for example, a lower
alkoxy such as methoxy, ethoxy or propoxy; an aralkyloxy such as
benzyloxy; a lower alkanoyloxy-lower alkoxy such as acetoxy
methoxy; or a heterocycle-lower alkoxy such as 2-pyridyl methoxy or
4-pyridylmethoxy.
The lower alkyl as R.sub.10 is as defined above. The halogen as
R.sub.10 is as defined above. The lower alkoxy as R.sub.10 is as
defined above for R.sub.5. The halogen as R.sub.10 is as defined
above for R.sub.5. The heterocycle group as Ar.sub.2 is, for
example, an imidazolyl such as 4-imidazolyl.
The substituted hydroxyl group as R.sub.14 is, for example, an
ether group such as a lower alkoxy defined as above, or an
optionally substituted aralkyl, for example, phenyl-lower alkyl
optionally substituted on the phenyl, such as benzyl, phenylpropyl,
4-methylbenzyl, 3,4-dichlorobenzyl, or an ester group, for example,
a lower alkanoyloxy such as acetoxy or propanoyloxy.
The substituted phenyl as R.sub.14 is, for example, a lower
alkylphenyl for example 3-methylpheny, a lower alkoxyphenyl such as
2,3- or a 4-methoxypheny, mono- or di-holophenyl such as
4-chlorophenyl, 3,4-dichlorophenyl.
The acyl as R.sub.14 is, for example, an acylphenyl such as
benzoyl, on an aralkylcarbonyl such as benzylcarbonyl or
phenylpropylcarbony.
The substituted alkoxycarbony R.sub.14 is, for example, a
phenyl-lower alkoxycarbonyl such as benzyloxycarbonyl, or
tert-butoxy carbonyl.
The substituted carbonyl is, for example, an arylcarbonyl such as
phenylcarbonyl, or an aralkyl carbonyl such as benzylcarbonyl.
The substituted amino R.sub.14 is, for example, a lower alkylamino,
an optionally substituted aralkylamine or N,N-lower alkyl
aralkylamino, for example, methylamino benzylamino,
3,4-dichlorobenzylamino, N,N-methyl benzylamino or N,N-methyl
3,4-dichloroamino.
The aryl sulfonyl R.sub.14 is, for example, benzylsulfonyl, a
isoquinolinesulfonyl.
The aralkylsulfonyl R.sub.14 is, for example, benzylsulfonyl or
phenyl propylsulfonyl.
The aralkyl R.sub.14 is, for example, benzyl or
phenylpropionyl.
The heterocyclyl group R.sub.14 is, for example, a pyridyl such as
2-pyridyl, or a pyrimidyl such as 2-pyrimidyl.
Since the present compounds have a nitrogen atom they can form
quaternary ammonium salts, or salts such as nontoxic salts. To form
a quaternary ammonium salt, a compound of the present invention is
reacted with, for example, methyl iodide. The salts of the present
invention are preferably nontoxicic salts, for example, salts with
an inorganic acid such as hydrochloric acid, sulfuric acid, nitric
acid, phosphorus acid, hydrogen bromide, hydrogen iodide or the
like, as well as salts with an organic acid, such as citric acid,
acetic acid, oxalic acid, tartaric acid, sulfonic acids such as
methane sulfonic acid, ethanesulfonic acid benzenesulfonic acid,
fumaric acid, maleic acid, malic acid or the like.
In an embodiment for the production of the present compounds, a
compound represented by the formula (IV) as described above is
reacted with a compound represented by the formula (V) as described
above.
In a preferable embodiment of this variation, a compound of the
formula (IV), wherein R.sub.1 and R.sub.3 represent a hydrogen
atom, is reacted, and after the reaction, the resulting
intermediate is derivatized, for example, alkylated or formulated
to introduce R.sub.1 and/or R.sub.3.
In a particular case, an isoquinolinesulfonamide represented by the
formula (IV'): ##STR10## is reacted with a compound of the formula
(V), and if necessary, the resulting intermediate is reduced. The
reaction is carried out, for example, in a medium such as methanol,
dimethylformamide, tetrahydrofuran, dimethy sulfoxide, diglyme,
benzene, at a temperature of 0.degree. C. to 100.degree. C.,
preferably a room temperature. The reduction is carried out using,
for example, sodium borohydride, aluminum lithium hydride or the
like, at a temperature of 0.degree. C. to 60.degree. C., preferably
at a room temperature. The introduction of R.sub.1 and/or R.sub.3
can be carried out by using a halide of R.sub.1 and/or R.sub.3,
i.e., Hal-R.sub.1 or Hal-R.sub.2 while removing hydrogen halide.
Where an alkylene halide is used, a compound wherein R.sub.1 and
R.sub.3 are linked is provided. For an introduction of formyl, the
intermediate is reacted with formic acid in the presence of acetic
anhidride. The above-mentioned reactions are carried out, for
example, in chloroform, dimethylacetamide, dimethylformamide or
other aprotic solvent, at a temperature of about 0.degree. C. to
100.degree. C., preferably at a room temperature.
In another embodiment for the production of the present compounds,
a compound of the formula (VI) is reacted with a compound (VII). In
a preferable embodiment, a compound of the formula (VI) wherein
R.sub.3 is hydrogen atom is reacted with a compound of the formula
(VII), and after the reaction, the resulting intermediate is
alkylated to introduce R.sub.3.
In a particular embodiment, a compound of the formula (VI')
##STR11## wherein R.sub.16 is an optional substituent on the phenyl
moiety W, is reacted with a compound of the formula (VII) to obtain
a compound represented by the formula (I-a): ##STR12##
The reaction is carried out in a medium such as pyridine,
dimethylformamide, acetonitrile, dioxane, tetrahydrofuran,
dichloromethane, chloroform or the like, at a temperature of about
0.degree. C. to 40.degree. C., preferably 20.degree. C. to
30.degree. C.
Note, the product (Ia) is reacted with a compound which introduces
the substituent R.sub.1 and/or R.sub.3. The compound which
introduces R.sub.1 and/or R.sub.3 is, for example, a halogen
compound of R.sub.1 or R.sub.3, i.e., Hal-R.sub.1 or Hal-R.sub.3
wherein Hal represents a halogen atom.
The reaction is carried out in a medium such as tetrahydrofuran,
dimethylformamide, dioxane, deethoxymethane, methanol, ether such
as ethyl ether, chloroform, ethyl acetate or the like in the
pressure of a base which kinds the resulting hydrogen halide during
the reaction, for example a tertiary amine such as pyridine,
dimethylaminopyridine. N-methylpiperidine or triethylamine, or an
inorganic base such as potassium bicarbonate, potassium hydroxide,
sodium carbonate, sodium hydroxide or the like.
The starting material (VI) wherein R is a hydrogen atom can be
obtained by reacting a compound represented by the formula (VIII):
##STR13## with a compound represented by the formula (IX):
For example, to obtain the intermediate (VI'), a compound of the
formula (VIII'): ##STR14## with a compound of the formula (IX'):
##STR15##
These reactions can be carried out under substantially the same
condition as for the introduction of R.sub.1 and R.sub.3.
In another embodiment for the production of the present compound
(I), a compound of the formula (VIII) is reacted with a compound of
the formula (VII).
The starting material (VIII) can be obtained by reacting a compound
represented by the formula (X): ##STR16## wherein R.sub.17 is a
hydrogen atom or a lower alkyl, with a compound represented by the
formula (XI): ##STR17##
By this reaction, the compound (VIII) wherein R.sub.12 and R.sub.13
together form .dbd.O is obtained. A reduction of this compound
provides the compound (VIII) wherein both R.sub.12 and R.sub.13
represent a hydrogen atom.
In a particular embodiment, a known compound tyrosine having the
amino group protected, and represented by the formula (Xa):
##STR18## is reacted with pyperazine having the nitrogen atom
protected is represented by the formula (XIa): ##STR19## to obtain
an intermediate represented by the formula (VIIIa): ##STR20##
Next, the intermediate (VIIIa) is then condensed with
isoquinolinesulfonylchloride to obtain a compound represented by
the formula (XII): ##STR21##
Next, the following modification of the compound (XII) can be
carried out to obtain some of the present compounds:
(2a) Hydrolysis to remove the isoquinolinesulfonyl group to free
hydroxy on the phenyl ring;
(3a) Deprotection of the piperazine ring;
(4a) Acylation or alkylation of the free hydroxy;
(4a) Acylation of the nitrogen atom of the piperazine moiety;
(5a) Alkylation of the sulfonamide group.
To prepare other compounds of the present invention, bistidine,
phenylalanine or the like can be used in place of tyrosine, and/or
piperidine or the like can be used in place of piperazine.
Moreover, an N-alkylated compound can be used in place of an
N-protected compound (IIa), and/or a hydroxy-protected compound of
the compound (IIa) can be used. The compound (VIIIa) or (XII) can
be reduced to convert the carbonyl structure to the methylene
chain. The orth portion of the phenyl ring can be linked with an
amino group via an alkylene chain to form a ring structure. Where
piperidine is used in place of piperazine, the piperidine moiety
can be converted to a corresponding moiety having an acetal
structure at the fourth position thereof. After condensation with a
sulfonic acid derivative, (8a) the acetal can be carbonylated, (6a)
the carbonyl can be converted to hydroxy or an amino group, (4b)
the hydroxyl or amino group can be acylated, or (5b) the hydroxyl
or amino group can be alkylated, to obtain some of the desired
compounds of the present invention.
The reaction of the compound (X) and (XI) is carried out in a
medium such as tetrahydrofuran, dioxane, dichloromethane, or other
aprotic solvent at a temperature of about 0.degree. C. to
40.degree. C., preferably 20.degree. C. to 30.degree. C.
The reaction of the compound (VII) and the compound (VIII) is
carried out in an aprotic solvent such as tetrahydrofuran,
methylene chloride, chloroform, dimethylformamide, or the like in
the presence of a hose such as triethylamine or the like at a
temperature of about 0.degree. C. to 40.degree. C., preferably
20.degree. C. to 30.degree. C.
The hydrolysis of step (2) is carried out in a solvent such as
methanol, tetrahydrofuran, a mixture thereof, dimethyl-sulfoxide or
the like, in the presence of a base such as sodium hydroxide,
potassium hydroxide or the like.
The reprotection of step (3) is carried out in a solvent such as
methanol, ethanol, chloroform, ethyl acetate or the like.
The acylation of step (4) is carried out in a solvent such as
chloroform, tetrahydrofuran, pyridine or the like, in the presence
of a base such as triethylamine.
The alkylation of step (5) is carried out in a solvent such as
dimethylformamide, tetrahydrofuran, ethyl acetate, methanol,
methylene chloride, or a mixture thereof.
The hydroxylation of step (6) is carried out in a protonic solvent
such as methanol or ethanol in the presence of a reducing agent
such as sodium borohydride, sodium cyanoborohydride. The amination
of step (6) is carried out, after an imine formation, under the
same condition as for the hydroxylation. The reduction of nitro in
step (7) is carried out in a solvent, for example, an alcohol such
as methanol or ethanol, by catalytic hydrogenation using as a
catalyst a noble methanol catalyst such as palladium on carbon.
The conversion of acetol to oxo is carried out by acidic hydrolysis
in an aqueous solution.
EXAMPLES
The present invention will now be further illustrated by, but is by
no means limited to, the following example.
In the Examples, melting points were determined by a melting point
measurement apparatus Yamato MP-21 (Yamato Kagaku, Japan) using a
capillary; nuclear magnetic resonance spectra (.sup.1 H-NMR) were
determined by JEOL.JNM-FX200 (Nippon Denshi, Japan); molecular
weights were determined by JMS-D300 type mass spectrometer (Nippon
Denshi, Japan); and infrared absorption spectra (IR) were
determined by IRA-1 (Nippon Bunko Kogyo, Japan).
REFERENCE EXAMPLE 1
1-[N-(Benzyloxycarbonyl)Histidyl]-4-Phenylpiperazine
7.13 g of N,N'-dibenzyloxycarbonyl histidine, 3.00 g of
4-phenylpiperazine and 16.1 g of N-hydroxybenzotriazole were
dissolved in 100 ml of tetrahydrofuran, and to the mixture was
added 3.84 g of DCC (dicyclohexylcarbodiimide), and the whole was
stirred at a room temperature for three hours. An insoluble matter
was filtered off, the filtrate was concentrated under a reduced
pressure, and to the concentrate was added 200 ml of ethyl acetate
to reform crystals, which were then filtered off. The filtrate was
sequentially washed with 20% potassium carbonate aqueous solution
and saturated sodium chloride aqueous solution, dried over
magnesium sulfate, and concentrated under a reduced pressure. The
resulting residue was dissolved in 60 ml of methanol, and after an
addition of a 10% ammonium-methanol solution and stirring at a room
temperature for 30 minutes, the solution was concentrated under a
reduced pressure to obtain a residue, which was then subjected to
silica gel chromatography and eluted with chloroform/methanol (50:1
to 10:1) to obtain 6.61 g of the title compound in a colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.81-3.20 (6H, m),
3.40-3.82 (4H, m), 4.95 (1H, m), 5.09 (2H, s), 5.78 (1H, d, J=8.3
Hz), 6.80-6.97 (4H, m), 7.20-7.30 (2H, m), 7.34 (5H, s), 7.55 (1H,
s).
REFERENCE EXAMPLE 2
1-[N-(Tert-Butoxycarbonyl)Histidyl]-4-Phenylpiperazine
6.61 g of 1-[N-(benzyloxycarbonyl)histidyl]-4-phenylpiperazine was
dissolved in 80 ml of methanol, and to the solution was added 4 g
of 5% palladium on carbon catalyst with ice cooling, and the
mixture was stirred under a hydrogen atmosphere at a room
temperature for 20 hours, and filtered to obtain a filtrate, which
was then concentrated under a reduced pressure to obtain 4.26 g of
a residue. The residue was dissolved in 80 ml of dimethylformamide,
and to the solution were sequentially added 6.8 g of
tert-butoxycarboxylic acid anhydride and 10 ml of triethylamine,
and the mixture was stirred at a room temperature for 90 minutes.
200 ml of ethyl acetate was added to the reaction mixture, which
was then washed twice with saturated sodium chloride aqueous
solution, dried over magnesium sulfate, and filtered to obtain a
filtrate. The filtrate was concentrated under a reduced pressure to
obtain a residue, which was then dissolved in 100 ml of methanol,
and to the resulting solution was added 20 ml of 10% sodium
hydroxide aqueous solution, and the whole was stirred at a room
temperature for 30 minutes. The reaction mixture was concentrated
under a reduced pressure to one third of the original volume, and
after the addition of 150 ml of water, the concentrate was
extracted twice with 80 ml each of chloroform, the resulting
chloroform phase was dried over magnesium sulfate, filtered, and
concentrated under a reduced pressure to obtain a residue. The
residue was applied on a silica gel column, and eluted with
chloroform/methanol (50:1 to 20:1) to obtain 4.53 g of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.43 (9H, s), 2.80-3.22
(6H, m), 3.40-3.83 (4H, m), 4.87 (1H, m), 5.46 (1H, br), 6.86-6.93
(4H, m), 7.23-7.31 (2H, m), 7.57 (1H, s).
REFERENCE EXAMPLE 3
1-[2-(Tert-Butoxycarbonylamino)-3-Imidazol-4(5)-Yl-Propyl]-4-Phenylpiperazi
ne
A solution of 1.3 g of lithium aluminum hydride in 38 ml of
tetrahydrofuran was added to a solution of 4.56 g of aluminum
chloride in 38 ml of ethyl ether with ice cooling, and the mixture
was stirred for 20 minutes with ice cooling. To the mixture was
dropwise added a solution of 4.53 g of
1-[N-(tert-butoxycarbonyl)histidyl]-4-phenylpiperazine in 51 ml of
tetrahydrofuran, and stirring for one hour with ice cooling, to the
reaction mixture was added 20 ml of 25% potassium carbonate aqueous
solution, followed by 100 ml of chloroform to obtain a suspension.
The suspension was filtered using silica as a filter aid to obtain
a filtrate. After the silica was washed with 20% methanol in
chloroform, the combined filtrate was concentrated under a reduced
pressure to obtain a residue. The residue was applied to a silica
gel column, and eluted with chloroform/methanol (40:1 to 10:1) to
obtain 3.1 g of the title compound in a colorless amorphous.
H-NMR (CDCl.sub.3, .delta. ppm): 1.44 (9H, s), 2.33 (1H, dd, J=7.3,
12.2 Hz), 2.47 (1H, dd, J=7.8, 12.2 Hz), 2.64 (4H, m), 2.93 (2H,
m), 3.20 (4H, m), 3.97 (1H, m), 5.10 (1H, br), 6.81-6.97 (4H, m),
7.21-7.30 (2H, m), 7.58 (1H, s).
EXAMPLE 1
N-{1-[1-(5-Isoquinolinesulfonyl)Imidazol-4(5)-Yl-Methyl]-2-(4-Phenylpiperaz
inyl)Ethyl}-5-Isoquinolinesulfonamide
3.1 g of the amorphous compound obtained in Reference Example 3 was
dissolved in 10 ml of ethyl acetate, and to the solution was added
16 ml of 4N hydrochloric acid in ethyl acetate was added, and the
mixture was stirred at a room temperature for 30 hours and
evaporated to dryness under a reduced pressure. To the residue were
added 70 ml of tetrahydrofuran and 30 ml of chloroform to form a
suspension, to which were added 6 g of isoquinolinesulfonic acid
chloride and 30 ml of triethylamine, and after stirring at a room
temperature for 18 hours, 150 ml of water was added and the whole
was extracted twice with 70 ml of chloroform. The extract was dried
over magnesium sulfate and concentrated under a reduced pressure to
obtain a residue, which was then applied to silica gel column, and
eluted with chloroform/methanol (80:1 to 60:1) to obtain 1.86 g of
the title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1618, 1600, 1490, 1380, 1325, 1210, 1170,
1132, 1073;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.00-2.34 (6H, m),
2.59-2.81 (6H, m), 3.39 (1H, m), 6.74-6.89 (3H, m), 7.04 (1H, d,
J=1.5 Hz), 7.19-7.29 (3H, m), 7.69 (1H, t, J=7.3 Hz), 7.80 (1H, t,
J=7.8 Hz), 7.93 (1H, d, J=1.5 Hz), 8.21 (1H, d, J=8.3 Hz), 8.34
(1H, d, J=8.3 Hz), 8.38-8.46 (3H, m), 8.52 (1H, dd, J=1.0, 7.3 Hz),
8.69 (1H, d, J=6.3 Hz), 8.77 (1H, d, J=6.3 Hz), 9.36 (1H, s), 9.39
(1H, s).
EXAMPLE 2
N-[1-(Imidazol-4(5)-Yl-Methyl)-2-(4-Phenylpiperazinyl)Ethyl]-5-Isoquinoline
Sulfonamide
250 mg of the amorphous compound obtained in Example 1 was
dissolved in a mixture of 1 ml of tetrahydrofuran and 5 ml of
methanol, and to the solution 1 ml of 4N sodium hydroxide was
added. After stirring at a room temperature for 10 minutes, 20 ml
of water was added to the mixture, which was then extracted twice
with a mixture of 10 ml of chloroform and 2 ml of isopropanol. The
extract was dried over magnesium sulfate, and concentrated under a
reduced pressure to obtain a residue, which was then applied to a
silica gel column, and eluted with chloroform/methanol (20:1) and
chloroform/methanol/triethylamine (20:1:0.2) to obtain 163 mg of
the title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1615, 1600, 1490, 1448, 1320, 1225, 1153,
1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.06-2.44 (6H, m),
2.67-2.90 (5H, m), 3.02 (1H, dd, J=5.4, 10.0 Hz), 3.25 (1H, m),
6.74-6.90 (4H, m), 7.19-7.33 (2H, m), 7.54 (1H, s), 7.74 (1H, t,
J=7.8 Hz), 8.24 (1H, d, J=7.8 Hz), 8.47 (1H, d, J=6.4 Hz), 8.52
(1H, dd, J=1.0, 7.32 Hz), 8.70 (1H, d, J=5.9 Hz), 9.38 (1H, s).
EXAMPLE 3
N-{1-[1-(5-Isoquinolinesulfonyl)Imidazol-4(5)-Yl-Methyl]-2-(Phenylpiperazin
yl)Ethyl}-N-Methyl-5-Isoquinoline Sulfonamide
1.45 g of the amorphous compound obtained in Example 1 was
dissolved in 20 ml of dimethylformamide, and to the solution were
sequentially added 120 mg of 60% sodium hydride and 0.2 ml of
methyl iodide with ice cooling, and after stirring for 30 minutes
with ice cooling, and 30 ml of water was added. After extraction of
the reaction mixture with 30 ml of ethyl acetate, the extract was
washed with saturated sodium chloride aqueous solution, dried over
magnesium sulfate and concentrated under a reduced pressure to
obtain a residue, which was then applied to a silica gel column and
eluted with chloroform/methanol (80:1) to obtain 616 mg of the
title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1618, 1600, 1490, 1380, 1320, 1210, 1170,
1140, 1080;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.35-2.47 (6H, m), 2.64
(1H, dd, J=7.8, 14.6 Hz), 2.80 (3H, s), 2.85-2.97 (5H, m), 4.36
(1H, m), 6.82-6.89 (3H, m), 7.08 (1H, d, J=1.5 Hz), 7.21-7.29 (2H,
m), 7.61 (1H, t, J=7.3 Hz), 7.75 (1H, t, J=7.8 Hz), 7.87 (1H, d,
J=1.5 Hz), 8.14 (1H, d, J=7.8 Hz), 8.25-8.29 (2H, m), 8.37-8.45
(3H, m), 8.64 (1H, d, J=5.9 Hz), 8.76 (1H, d, J=6.3 Hz), 9.31 (1H,
s), 9.35 (1H, s).
EXAMPLE 4
N-[1-(Imidazol-4(5)-Yl-Methyl)-2-(4
-Phenylpiperazinyl)Ethyl]-N-Methyl-5-Isoquinoline Sulfonamide
450 mg of the amorphous compound obtained in Example 3 was
dissolved in a mixture of 2 ml of tetrahydrofuran and 10 ml of
methanol, and to the solution was added 1 ml of 4N sodium
hydroxide. After stirring at a room temperature for 10 minutes, the
reaction mixture was worked up according to the same procedure as
described in Example 2 to obtain 299 mg of the title compound in a
colorless amorphous form.
IR (KBr) cm.sup.-1 : 1595, 1490, 1448, 1320, 1225, 1150, 1128;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.45-2.65 (6H, m), 2.89
(3H, s), 2.90-3.08 (6H, m), 4.37 (1H, m), 6.68 (1H, s), 6.82-6.90
(3H, m), 7.20-7.32 (3H, m), 7.64 (1H, t, J=7.8 Hz), 8.14 (1H, d,
J=7.8 Hz), 8.31 (1H, d, J=6.3 Hz), 8.46 (1H, dd, J=1.0, 7.3 Hz),
8.62 (1H, d, J=5.9 Hz), 9.29 (1H, s).
REFERENCE EXAMPLE 4
N-(Tert-Butoxycarbonyl)-3,4-Dibenzytloxyphenylalanine Benzyl
Ester
21.12 g of N-(tert-butoxycarbonyl) DOPA was dissolved in 200 ml of
dimethylformamide, and after 50 g of benzyl bromide and 40 g of
potassium carbonate were added, the mixture was stirred at a room
temperature for 40 hours. After the addition of 400 ml of sodium
chloride aqueous solution, the reaction mixture was extracted with
500 ml of ethyl acetate, and the extract was washed twice with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate, filtered, and concentrated under a reduced pressure To the
resulting residue was added hexane to crystallize the title
compound, which was then washed, filtered and dried to obtain 30.0
g of the colorless crystals
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.42 (9H, s), 2.99 (2H, d,
J=14.14 Hz), 4.59 (1H, m), 4.98 (1H, brd), 5.05 (2H, s), 5.07 (2H,
s), 5.11 (2H, s), 6.56 (1H, dd, J=2.0, 7.8 Hz), 6.71 (1H, d, J=2.0
Hz), 6.79 (1H, d, J=7.8 Hz), 7.20-7.50.
REFERENCE EXAMPLE 5
N-(Tert-Butoxycarbonyl)-3,4-Dibenzyloxyphenylalanine
30.0 g of the crystals obtained in Example 4 was dissolved in 600
ml of methanol, and after the addition of 65 ml of 10% sodium
hydroxide, the mixture was stirred at a room temperature for 20
hours, and 1000 ml of water was added. The reaction mixture was
adjusted to pH 4 with concentrated hydrochloric acid, and extracted
twice with 800 ml of chloroform. The extract was dried over
magnesium sulfate and concentrated under a reduced pressure to
crystallize the title compound, which was then filtered and washed
with hexane to obtain 25.2 g of colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.40 (9H, s), 3.02 (2H, m),
4.49 (1H, brs), 4.88 (1H, brs), 5.11 (4H, s), 6.68 (1H, dd, J=2.0,
7.8 Hz), 6.76 (1H, d, J=2.0 Hz), 6.74 (1H, d, J=7.8 Hz), 7.23-7.45
(10H, m).
REFERENCE EXAMPLE 6
1-[N-(Tert-Butoxycarbonyl)-3,4-Dibenzyloxyphenylalaninyl]-4-Phenylpiperazin
e
5.67 g of the crystals obtained in Reference Example 5, 1.9 g of
N-phenylpiperazine and 1.53 g of N-hydroxybenzotriazole were
dissolved in 80 ml of methylene chloride, and after the addition of
2.4 g of DCC, the mixture was stirred at a room temperature for 18
hours. Resulting insoluble matter was filtered off, and washed with
ethyl acetate.
The combined filtrate was concentrated under a reduced pressure to
obtain a residue, which was then applied to a silica gel column,
and eluted with hexane/ethyl acetate (2:1) to obtain 6.39 g of the
title compound as colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.44 (9H, s), 2.39 (1H, m),
2.76-3.10 (6H, m), 3.30 (1H, m), 3.61 (2H, m), 4.78 (1H, m), 5.03
(2H, s), 5.14 (2H, s), 5.42 (1H, brd, J=8.3 Hz), 6.69 (1H, dd,
J=2.0, 8.3 Hz), 6.79-6.91 (5H, m), 7.20-7.48 (12H, m).
REFERENCE EXAMPLE 7
1-{2-N-(Tert-Butoxycarbonylamino)]-3-(3,4-Dibenzyloxyphenyl)Propyl}-4-Pheny
lpiperazine
3.66 g of the colorless amorphous obtained in Reference Example 6
was dissolved in 50 ml of tetrahydrofuran, and the addition of 700
mg of lithium aluminum hydride with ice cooling, the mixture was
stirred for 90 minutes with ice cooling, and to the mixture was
added water until foaming ended. Then 80 ml of chloroform was added
to the reaction mixture to form a suspension, which was then
filtered using silica gel as a filter acid to remove insoluble
matter. The resulting filtrate was concentrated under a reduced
pressure to obtain a residue, which was then applied to a silica
gel column, and eluted with hexane/ethyl acetate (3:1) to obtain
2.67 g of the title compound in colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.43 (9H, s), 2.24 (2H, m),
2.53 (4H, m), 2.79 (2H, m), 3.16 (4H, m), 3.90 (1H, m), 4.58 (1H,
brs), 5.13 (2H, s), 5.16 (2H, s), 6.70 (1H, dd, J=2.0, 8.3 Hz),
6.80-6.93 (5H, m), 7.20-7.46 (12H, m).
REFERENCE EXAMPLE 8
1-[2-Amino-3-(3,4-Dibenzyloxyphenyl)Propyl]-4-Phenylpiperazine
4.35 g of the amorphous compound obtained in Reference Example 7
was dissolved in 20 ml of ethyl acetate, and after the addition of
30 ml of 4N hydrochloric acid in ethyl acetate, the mixture was
stirred at a room temperature for one hour. The reaction mixture
was concentrated under a reduced pressure, alkalized with sodium
bicarbonate aqueous solution, and extracted twice with 80 ml of
chloroform, and the extract was dried over magnesium sulfate and
concentrated under a reduced pressure. The resulting residue was
applied to a silica gel column and eluted with chloroform-methanol
(100:1 to 30:1) to obtain 1.64 g of the title compound in a
colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.27-2.68 (8H, m),
3.10-3.20 (5H, m), 5.10 (2H, brs), 5.14 (2H, s), 5.17 (2H, s), 6.73
(1H, dd, J=2.0, 8.3 Hz), 6.81-6.94 (5H, m), 7.22-7.46 (12H, m).
EXAMPLE 5
N-{1-[(3,4-Dibenzyloxyphenyl)Methyl]-2-(4-Phenylpiperazinyl)Ethyl}-5-Isoqui
noline Sulfonamide
640 mg of the amorphous compound obtained in Reference Example 8
was dissolved in 15 ml of methylene chloride, and to the solution
were added 1 ml of triethylamine and 350 mg of
5-isoquinolinesulfonyl chloride with ice cooling, and after
stirring for one hour with ice cooling, was added 50 ml of water,
and the mixture was extracted twice with 50 ml of chloroform. The
extract was dried over magnesium sulfate and concentrated under a
reduced pressure to obtain a residue, which was then applied to a
silica gel column and eluted with hexane/ethyl acetate (1:1) to
obtain 470 mg of the title compound in a colorless amorphous
form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.08-2.24 (6H, m),
2.64-2.91 (6H, m), 3.30 (1H, m), 5.08 (2H, s), 5.10 (2H, s), 6.51
(1H, dd, J=2.0, 8.3 Hz), 6.63 (1H, d, J=2.0 Hz), 6.71 (1H, d, J=8.3
Hz), 6.76-6.89 (3H, m), 7.21-7.43 (12H, m), 7.67 (1H, t, J=7.8 Hz),
8.18 (1H, d, J=8.3 Hz), 8.44 (2H, m), 8.67 (1H, d, J=5.9 Hz), 9.34
(1H, s).
EXAMPLE 6
N-{1-[(3,4-Dibenzyloxyphenyl)Methyl]-2-(4-Phenylpiperazinyl)Ethyl}-N-Methyl
-5-Isoquinoline Sulfonamide
470 mg of the amorphous compound obtained in Example 5 was
dissolved in 8 ml of dimethylformamide, and to the solution were
sequentially added 30 mg of 60% sodium hydride and 0.1 ml of methyl
iodide with ice cooling, and after stirring for two hours with ice
cooling was added saturated sodium chloride, and the mixture was
extracted with 50 ml of ethyl acetate. The extract was washed with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate and concentrated under a reduced pressure to obtain a
residue, which was then applied to a silica gel column and eluted
with hexane/ethyl acetate (1:1) to obtain 413 mg of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.34 (1H, dd, J=6.35, 13.2
Hz), 2.42-2.60 (5H, m), 2.65 (1H, dd, J=7.3, 14.2 Hz), 2.81 (1H,
dd, J=6.4, 14.2 Hz), 2.86 (3H, s), 2.99 (4H, m), 4.22 (1H, m), 5.03
(2H, s), 5.10 (2H, s), 6.54 (1H, dd, J=2.0, 8.3 Hz), 6.61 (1H, d,
J=2.0 Hz), 6.63 (1H, d, J=8.3 Hz), 6.82-6.90 (3H, m), 7.19-7.53
(13H, m), 8.05 (1H, d, J=8.3 Hz), 8.24 (1H, dd, J=1.0, 7.3 Hz),
8.30 (1H, d, J=5.9 Hz), 8.60 (1H, d, J=5.9 Hz), 9.24 (1H, d, J=1.0
Hz).
EXAMPLE 7
N-{1-[(3,4-Dihydroxyphenyl)Methyl]-2-(4-Phenylpiperazinyl)Ethyl}-N-Methyl-I
soquinoline Sulfonamide
310 mg of the amorphous compound obtained in Example 6 was
dissolved in 2 ml of 1,2-ethanedithiol, and to the solution were
added 1 ml of boron trifluoride/ethyl ether, and after stirring at
a room temperature for 18 hours, was added saturated sodium
bicarbonate aqueous solution, and the reaction mixture was
extracted twice with a mixture of chloroform and methanol (10:1).
The extract was dried over magnesium sulfate, and concentrated
under a reduced pressure to obtain a residue, which was applied to
a silica gel column and eluted with chloroform/methanol (80:1 to
20:1) to obtain 148 mg of the title compound in a colorless
amorphous form.
IR (KBr) cm.sup.-1 : 1600, 1495, 1448, 1328, 1230, 1155, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.41 (1H, dd, J=10.25,
14.65 Hz), 2.50-2.98 (7H, m), 3.01 (3H, s), 3.17 (4H, m), 4.06 (1H,
m), 6.12 (1H, dd, J=20, 8.3 Hz), 6.20 (1H, d, J=8.3 Hz), 6.28 (1H,
d, J=2.0 Hz), 6.82-6.95 (3H, m), 7.26 (2H, m), 7.62 (1H, t, J=7.8
Hz), 8.09 (1H, d, J=6.8 Hz), 8.13 (1H, d, J=9.3 Hz), 8.30 (1H, d,
J=6.8 Hz), 8.41 (1H, d, J=4.9 Hz), 9.25 (1H, s).
EXAMPLE 8
N-{1-[(3,4-Dihydroxyphenyl)Methyl]-2-(4-Phenylpiperazinyl)Ethyl}-5-Isoquino
line Sulfonamide
The amorphous compound obtained in Example 5 was treated according
to the procedure as described in Example 7 to obtain the title
compound in colorless amorphous form.
IR (KBr) cm.sup.-1 : 1610, 1600, 1490, 1445, 1320, 1220, 1150,
1128;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.30-2.60 (6H, m),
2.74-3.02 (6H, m), 3.36 (1H, m), 6.15 (1H, d, J=8.3 Hz), 6.33 (1H,
d, J=8.3 Hz), 6.36 (1H, s), 6.76-6.90 (3H, m), 7.19-7.29 (2H, m),
7.65 (1H, t, J=7.8 Hz), 8.16 (1H, d, J=8.3 Hz), 8.33 (1H, d, J=6.5
Hz), 8.39 (1H, d, J=7.3 Hz), 8.51 (1H, d, J=5.5 Hz), 9.28 (1H,
s).
REFERENCE EXAMPLE 9
6,7-Dibenzyloxy-3-[(4-Phenylpiperazinyl)Methyl]-1,2,3,4-Tetrahydroisoquinol
ine
1.00 g of the amorphous compound obtained in Reference Example 8
was dissolved in 2 ml of tetrahydrofuran, and to the solution was
added 0.25 ml of 37% formalin. After stirring at a room temperature
for 30 minutes, 600 mg of 12N hydrochloric acid was added to the
mixture, which was then stirred at a room temperature for two
hours. After the addition of saturated sodium bicarbonate aqueous
solution, the reaction mixture was extracted twice with 20 ml of
chloroform. The extract was dried over magnesium sulfate, and
concentrated under a reduced pressure to obtain a residue, which
was then applied to a silica gel column and eluted with
chloroform/methanol (100:1) to obtain 585 mg of the title compound
in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.28-2.38 (8H, m), 3.02
(1H, m), 3.21 (4H, m), 3.95 (2H, s), 5.11 (4H, s), 6.63 (1H, s),
6.68 (1H, s), 6.80-6.95 (3H, m), 7.20-7.46 (12H, m).
EXAMPLE 9
6,7-Dibenzyloxy-2-(5-Isoquinolinesulfonyl)-3-[(4-Phenylpiperazinyl)Methyl]-
1,2,3,4-Tetrahydroisoquinoline
580 mg of the amorphous compound obtained in Reference Example 9
was dissolved in 10 ml of methylene chloride, and to the solution
were added 1 ml of triethylamine and 400 mg of 5-isoquinoline
sulfonyl chloride.HCl with ice cooling. The mixture was stirred at
a room temperature for two hours, and after the addition of 20 ml
of water, extracted twice with 10 ml of chloroform. The extract was
dried over magnesium sulfate and concentrated under reduced
pressure to obtain a residue, which was then applied to a silica
gel column and eluted with hexane/ethyl acetate (1:1) to obtain 610
mg of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.31 (1H, dd, J=7.8, 11.6
Hz), 2.43 (1H, dd, J=6.8, 11.6 Hz), 2.53 (4H, m), 2.70 (1H, dd,
J=2.0, 16.2 Hz), 2.87 (1H, dd, J=4.2, 16.2 Hz), 3.05 (4H, m), 4.26
(1H, d, J=15.6 Hz), 4.48 (1H, d, J=15.6 Hz), 4.49 (1H, m), 5.06
(2H, s), 5.07 (2H, s), 6.56 (1H, s), 6.60 (1H, s), 6.80-6.90 (3H,
m), 7.20-7.95 (12H, m), 7.64 (1H, t, J=7.8 Hz), 8.15 (1H, d, J=7.81
Hz), 8.37 (1H, d, J=5.9 Hz), 8.48 (1H, dd, J=1.0, 7.3 Hz), 8.64
(1H, d, J=6.4 Hz), 9.30 (1H, d, J=1.0 Hz).
EXAMPLE 10
6,7-Dihydroxy-2-(5-Isoquinolinesulfonyl)-3-[(4-Phenylpiperazinyl)methyl]-1,
2,3,4-tetrahydroisoquinoline
To 314 mg of the amorphous compound obtained in Example 9, were
added 2 ml of 1,2-ethanedithiol and 1 ml of boron trifluoride/ethyl
ether, and the mixture was stirred at a room temperature for 18
hours. After the addition of saturated sodium bicarbonate aqueous
solution, the reaction mixture was extracted twice with a mixture
of chloroform and methanol (1:1), and the extract was dried over
magnesium sulfate and concentrated under a reduced pressure to
obtain a residue, which was then applied to a silica gel column and
eluted with chloroform/methanol (50:1 to 20:1) to obtain 213 mg of
the title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1610, 1600, 1490, 1445, 1320, 1225, 1150,
1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.35-2.80 (8H, m), 3.11
(4H, m), 4.24 (1H, d, J=16.1 Hz), 4.40 (1H, d, J=16.1 Hz), 4.55
(1H, m), 6.45 (2H, s), 6.80-6.90 (3H, m), 7.20-7.28 (2H, m), 7.67
(1H, t, J=7.8 Hz), 8.14 (1H, d, J=8.5 Hz), 8.40 (1H, d, J=6.3 Hz),
8.50 (1H, dd, J=1.0, 7.3 Hz), 8.59 (1H, d, J=6.4 Hz), 9.25 (1H, d,
J=1.0 Hz).
REFERENCE EXAMPLE 10
1-[N-(Tert-Butoxycarbonyl)-P-Nitrophenylalanyl]-4-Phenylpiperazine
7.03 g of p-nitrophenylalanine was suspended in 70 ml of
1,4-dioxane, and to the suspension were added 28 ml of 10% sodium
hydroxide aqueous solution and 7.5 g of di-tert-butyl-dicarbonate,
and the mixture was stirred at a room temperature for 30 minutes.
200 ml of water and 7 ml of 12N hydrochloric acid were added to the
reaction mixture, which was then extracted with 150 ml of ethyl
acetate, and the extract was washed with saturated sodium chloride
aqueous solution, dried over magnesium sulfate, and concentrated
under a reduced pressure. The resulting residue was dissolved in
150 ml of tetrahydrofuran, and to the solution were added 6.0 g of
N-phenylpiperazine and 5.5 g of N-hydroxybenzotriazole, and further
added 7.6 g of DCC. After stirring at a room temperature for three
hours, the reaction mixture was filtered to remove insoluble matter
and the filtrate was concentrated under a reduced pressure, and the
resulting residue was dissolved in 200 ml of ethyl acetate. The
solution was sequentially washed with 10% potassium carbonate
aqueous solution and saturated sodium chloride aqueous solution,
dried over magnesium sulfate, and concentrated under a reduced
pressure to obtain a residue, which was then applied to a silicon
gel column and eluted with hexane/ethyl acetate (2:1) to obtain
11.1 g of the title compound as pale yellow crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.40 (9H, s), 2.83-3.20
(6H, m), 3.37 (1H, m), 3.57-3.70 (3H, m) , 3.84 (1H, m), 4.92 (1H,
m,), 5.40 (1H, d, J=8.3 Hz), 6.85-6.95 (3H, m), 7.24-7.32 (2H, m),
7.38 (2H, d, J=8.8 Hz), 8.16 (2H, d, J=8.8 Hz).
EXAMPLE 11
1-[N-(5-Isoquinolinesulfonyl)-P-Nitrophenylalanyl]-4-Phenylpiperazine
11.0 g of the crystals obtained in Reference Example 10 was
dissolved in 100 ml of ethyl acetate, and after the addition of 100
ml of 4N hydrochloric acid in ethyl acetate, the reaction mixture
was stirred at a room temperature for one hour and concentrated to
dryness under a reduced pressure. To the residue was added 200 ml
of saturated sodium bicarbonate, and the mixture was extracted
twice with 100 ml of chloroform. The extract was dried over
magnesium sulfate and concentrated under a reduced pressure to
obtain a residue, which was then applied to a silica gel column and
eluted with chloroform/methanol (80:1 to 10:1) to obtain free
amine. The free amine was dissolved in 100 ml of methylene
chloride, and to the solution were sequentially added 8.5 g of
5-isoquinoline sulfonyl chloride.HCl and 20 ml of triethylamine.
The reaction mixture was stirred at a room temperature for 18
hours, and after the addition of water, extracted twice with 100 ml
of chloroform. The extract was dried over magnesium sulfate and
concentrated under a reduced pressure to obtain a residue, which
was then applied to a silica gel column and eluted with
chloroform/methanol (100:1 to 50:1) to obtain 9.66 g of the title
compound as colorless crystals.
Melting point: 184.degree.-188.degree. C. (decomposed);
IR (KBr) cm.sup.-1 : 1660, 1600, 1520, 1420, 1345, 1325, 1230,
1150, 1135;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.72-3.06 (6H, m),
3.20-3.61 (4H, m), 4.46 (1H, m), 6.06 (1H, br), 6.83 (2H, d, J=7.8
Hz), 6.94 (1H, t, J=7.3 Hz), 7.10 (2H, t, J=8.8 Hz), 7.29 (2H, m),
7.56 (1H, t, J=7.8 Hz), 7.82 (2H, d, J=8.8 Hz), 8.09 (1H, d, J=7.8
Hz), 8.22-8.29 (2H, m), 8.71 (1H, d, J=6.3 Hz), 9.26 (1H, s).
EXAMPLE 12
1-[N-(5-Isoquinolinesulfonyl)-N-Methyl-P-Nitrophenylalanyl]-4-Phenylpiperaz
ine
5.87 g of the crystals obtained in Example 11 was dissolved in 60
ml of dimethylformamide, and to the solution were sequentially
added 500 mg of 60% sodium hydride and 1.5 ml of methyl iodide with
ice cooling. After stirring for two hours with ice cooling, water
was added to the reaction mixture, which was then extracted with
150 ml of ethyl acetate. The extract was washed with saturated
sodium chloride aqueous solution, dried over magnesium sulfate and
concentrated under a reduced pressure to obtain a residue, which
was applied to a silica gel column and eluted with
chloroform/methanol (100:1) to obtain 5.93 g of the title compound
in a yellow amorphous form.
IR (KBr) cm.sup.-1 : 1640, 1600, 1535, 1445, 1340, 1225, 1150,
1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.60 (1H, dd, J=4.9, 12.7
Hz), 2.83 (1H, m), 2.92-3.06 (3H, m), 3.06 (3H, s), 3.40 (1H, dd,
J=7.8, 13.2 Hz), 3.46-3.63 (2H, m), 3.70-3.88 (2H, m), 5.23 (1H,
dd, J=4.9, 9.8 Hz), 6.82 (2H, d, J=7.8 Hz), 6.91 (1H, t, J=7.3 Hz),
7.22-7.30 (4H, m), 7.73 (1H, t, J=7.8 Hz), 8.07 (2H, d, J=8.8 Hz),
8.25 (1H, d, J=8.3 Hz), 8.36 (1H, dd, J=1.0, 7.3 Hz), 8.48 (1H, d,
J=6.4 Hz), 8.71 (1H, d, J=6.4 Hz), 9.37 (1H, d, J=1.0 Hz).
EXAMPLE 13
1-[P-Amino-N-(5-Isoquinolinesulfonyl)-N-Methylalanyl]-4-Phenylpiperazine
6.08 g of the amorphous compound obtained in Example 12 was
dissolved in 70 ml of methanol, and to the solution were added 5 ml
of 12N hydrochloric acid and 30 ml of water, and then 5 g of 5%
palladium on carbon. The mixture was stirred at a room temperature
under a hydrogen atmosphere for 30 minutes, and filtered to remove
insoluble matter, and the filtrate was concentrated under a reduced
pressure, and to the residue was added 150 ml of saturated sodium
bicarbonate aqueous solution, and the mixture was extracted twice
with 200 ml of chloroform. The extract was dried over magnesium
sulfate and concentrated under a reduced pressure to obtain a
residue, which was then applied to a silica gel column and eluted
with chloroform/methanol (50:1) to obtain 3.32 g of the title
compound in a yellow amorphous form.
IR (KBr) cm.sup.-1 : 1635, 1600, 1495, 1445, 1325, 1220, 1150,
1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.47-2.56 (2H, m),
2.87-3.22 (4H, m), 3.14 (3H, s), 3.33-3.75 (4H, m), 5.14 (1H, dd,
J=4.9, 9.8 Hz), 6.50 (2H, d, J=8.3 Hz), 6.80-6.92 (5H, m),
7.22-7.34 (2H, m), 7.69 (1H, t, J=7.8 Hz), 8.20 (1H, d, J=8.3 Hz),
8.36 (1H, dd, J=1.5, 7.3 Hz), 8.40 (1H, d, J=5.9 Hz), 8.68 (1H, d,
J=6.4 Hz), 9.34 (1H, s).
EXAMPLE 14
3.75 g of the crystal prepared in Example 11 was treated according
to the procedure as described in Example 13 to obtain 2.17 g of
1-[p-amino-N-(5-isoquinolinesulfonyl)phenylalanyl]-4-phenylpiperazine
as yellow crystals.
IR (KBr) cm.sup.-1 : 1635, 1600, 1495, 1440, 1320, 1225, 1155,
1135;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.41 (1H, m), 2.59-3.07
(6H, m), 3.17 (1H, m), 3.33 (1H, m), 3.51 (1H, m), 4.35 (1H, m),
5.95 (1H, d, J=9.3 Hz), 6.38 (2H, d, J=8.3 Hz), 6.75 (2H, d, J=8.3
Hz), 6.78 (2H, d, J=7.8 Hz), 6.91 (1H, t, J=7.3 Hz), 7.22-7.30 (2H,
m), 7.60 (1H, t, J=8.3 Hz), 8.12 (1H, d, J=8.3 Hz), 8.30-8.35 (2H,
m), 8.71 (1H, d, J=5.9 Hz), 9.30 (1H, s).
EXAMPLE 15
1-[N-(5-Isoquinolinesulfonyl)-P-(P-Toluenesulfonylamino)Phenylalanyl]-4-Phe
nylpiperazine
200 mg of the crystals obtained in Example 14 was dissolved in 5 ml
of pyridine, and to the solution was added 90 mg of
p-toluenesulfonylchloride with ice cooling, and the mixture was
stirred for one hour with ice cooling and poured to 30 ml of
saturated sodium bicarbonate aqueous solution. The mixture was
extracted twice with 15 ml of chloroform, and the extract was dried
over magnesium sulfate and concentrated under a reduced pressure to
obtain a residue, which was then applied to a silica gel column and
eluted with chloroform/methanol (80:1 to 50:1) to obtain 128 mg of
the title compound.
IR (KBr) cm.sup.-1 : 1635, 1600, 1335, 1225, 1155, 1090;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.30 (3H, s), 2.65-2.80
(4H, m), 2.83-3.04 (2H, m), 3.17-3.50 (4H, m), 4.33 (1H, m), 6.14
(1H, d, J=9.3 Hz), 6.70-6.83 (6H, m), 6.93 (1H, t, J=7.3 Hz), 6.77
(1H, s), 7.17 (2H, d, J=8.3 Hz), 7.26-7.36 (2H, m), 7.59 (1H, t,
J=7.3 Hz), 7.59 (2H, d, J=8.3 Hz), 8.13 (1H, d, J=7.8 Hz), 8.30
(2H, m), 8.64 (1H, br), 9.31 (1H, br).
EXAMPLE 16
The same procedure as described in Example 15 was repeated, except
that 200 mg of 5-isoquinolinesulfonyl chloride.HCl and 300 mg of
the crystals obtained in Example 14 were used and elution was
carried out with chloroform/methanol (40:1 to 20:1), to obtain 372
mg of
1-[N-(5-isoquinolinesulfonyl)-p-(5-isoquinolinesulfonylamino)phenylalanyl]
-4-phenylpiperazine.
IR (KBr) cm.sup.-1 : 1630, 1600, 1340, 1225, 1155, 1135;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.35-3.07 (9H, m), 3.30
(1H, m), 4.26 (1H, m), 6.67-6.84 (6H, m), 6.89-6.96 (2H, m), 7.23
(2H, t, J=8.8 Hz), 7.52 (1H, t, J=7.8 Hz), 7.54 (1H, t, J=7.8 Hz),
7.98 (1H, d, J=7.8 Hz), 8.07 (1H, d, J=8.3 Hz), 8.25 (1H, d, J=6.8
Hz), 8.31-8.36 (2H, m), 8.54 (1H, d, J=6.3 Hz), 8.65 (2H, d, J=6.4
Hz), 9.17 (1H, s), 9.26 (1H, s), 10.06 (1H, s).
EXAMPLE 17
The same procedure as described in Example 15 was repeated, except
that 200 mg of 1-naphtharenesulfonyl chloride and 360 mg of the
crystals obtained in Example 14 were used as starting materials and
elution was carried out using chloroform/methanol (80:1 to 50:1),
to obtain 385 mg of
1-[N-(5-isoquinolinesulfonyl)-p-(1-naphtharenesulfonylamino)phenylalanyl]-
4-phenylpiperazine.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.40-2.74 (6H, m),
2.80-3.04 (3H, m) 3.33 (1H, m), 4.24 (1H, m), 6.68-6.82 (6H, m),
6.92 (1H, t, J=7.3 Hz), 7.12 (1H, d, J=9.3 Hz), 7.26-7.57 (5H, m),
7.65 (1H, m), 7.78 (1H, d, J=8.3 Hz), 7.88 (1H, d, J=7.8 Hz), 7.99
(1H, d, J=8.3 Hz), 8.16 (1H, dd, J=1.0, 7.3 Hz), 8.21 (1H, dd,
J=1.0, 7.3 Hz), 8.36 (1H, d, J=5.9 Hz), 8.65 (1H, d, J=6.4 Hz),
8.77 (1H, d, J=8.8 Hz), 9.22 (1H, s), 9.88 (1H, s).
EXAMPLE 18
The same procedure as described in Example 15 was repeated, except
that 0.07 ml of methanesulfonyl chloride and 360 mg of the crystals
obtained in Example 14 were used as starting materials and elution
was carried out using chloroform/methanol (50:1 to 30:1), to obtain
356 mg of
1-[N-(5-isoquinolinesulfonyl)-p-(methanesulfonylamino)phenylalanyl]-4-phen
ylpiperazine.
IR (KBr) cm.sup.-1 : 1635, 1600, 1330, 1225, 1150;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.38 (1H, m), 2.72 (3H, s),
2.70-2.90 (6H, m), 3.04-3.21 (3H, m), 3.42 (1H, m), 4.39 (1H, m),
6.78 (2H, d, J=7.8 Hz), 6.88 (1H, t, J=7.3 Hz), 6.92 (2H, d, J=8.3
Hz), 7.00 (2H, d, J=8.3 Hz), 7.20-7.30 (3H, m), 7.62 (1H, t, J=7.8
Hz), 8.16 (1H, d, J=8.3 Hz), 8.32 (1H, dd, J=1.0, 7.3 Hz), 8.42
(1H, d, J=5.9 Hz), 8.69 (1H, d, J=6.4 Hz), 9.15 (1H, s), 9.31 (1H,
s).
EXAMPLE 19
1-[N-(5-Isoquinolinesulfonyl)-P-Methanesulfonylamino-N-Methylphenylalanyl]-
4-Phenylpiperazine
700 mg of the amorphous compound obtained in Example 13 was
dissolved in 7 ml of pyridine, and to the solution was added 0.13
ml of methanesulfonyl chloride with ice cooling, and the mixture
was stirred for one hour with ice cooling and poured to 50 ml of
saturated sodium bicarbonate aqueous solution. The mixture was
extracted twice with 30 ml of chloroform. The extract was dried
over magnesium sulfate and concentrated under a reduced pressure.
The resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1 to 50:1) to obtain 790 mg of the
title compound.
IR (KBr) cm.sup.-1 : 1635, 1595, 1325, 1220, 1145;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.48-2.59 (2H, m), 2.83
(3H, s), 2.85-3.10 (3H, m), 3.12 (3H, s), 3.22 (1H, dd, J=9.8, 13.2
Hz), 3.44-3.80 (4H, m), 5.16 (1H, dd, J=5.4, 9.8 Hz), 6.80-6.93
(4H, m), 7.04 (4H, s), 7.26 (2H, t, J=8.3 Hz), 7.72 (1H, t, J=7.8
Hz), 8.23 (1H, d, J=8.3 Hz), 8.35 (1H, dd, J=1.0, 7.3 Hz) 8.42 (1H,
d, J=5.9 Hz), 8.68 (1H, d, J=5.9 Hz), 9.36 (1H, s).
EXAMPLE 20
The same procedure as described in Example 19 was repeated, except
that 360 mg of 1-naphtharenesulfonyl chloride and 700 mg of the
amorphous compound obtained in Example 13 were used as starting
materials, and elution was carried out using chloroform/methanol
(100:1) to obtain 770 mg of
1-[N-(5-isoquinolinesulfonyl)-N-methyl-p-(1-naphtharenesulfonylamino)pheny
lalanyl]-4-phenylpiperazine.
IR (KBr) cm.sup.-1 : 1635, 1595, 1440, 1330, 1220, 1150, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.42 (1H, dd, J=4.9, 12.7
Hz), 2.63 (1H, m), 2.85-3.17 (4H, m), 3.07 (3H, s), 3.32-3.73 (4H,
m), 5.04 (1H, dd, J=5.4, 10.3 Hz), 6.73-6.96 (7H, m), 7.05 (1H,
br), 7.30-7.41 (3H, m) 7.54-7.70 (3H, m), 7.88 (1H, d, J=7.8 Hz),
7.95 (1H, d, J=8.3 Hz), 8.12 (1H, dd, J=1.0, 7.3 Hz), 8.16 (1H, d,
J=8.3 Hz), 8.27 (1H, dd, J=1.5, 7.3 Hz), 8.37 (1H, d, J=6.3 Hz),
8.62-8.68 (2H, m), 9.32 (1H, s).
EXAMPLE 21
The same procedure as described in Example 19 was repeated except
that 320 mg of 5-isoquinolinesulfonyl chloride.HCL as a sulfonating
agent, 500 mg of the amorphous compound obtained in Example 13, 5
ml of pyridine and chloroform/methanol (80:1 to 50:1) as an eluent
were used, to obtain 498 mg of
1-[N-(5-isoquinolinesulfonyl)-p-(5-isoquinolinesulfonylamino)-N-methylphen
ylalanyl]-4-phenylpiperazine.
IR (KBr) cm.sup.-1 : 1640, 1595, 1330, 1225, 1155, 1135.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.44 (1H, dd, J=4.9, 13.2
Hz), 2.61 (1H, m), 2.85-3.26 (5H, m), 3.05 (3H, s), 3.40-3.70 (3H,
m), 5.06 (1H, dd, J=4.9, 9.8 Hz), 6.77 (2H, d, J=8.8 Hz), 6.79-6.97
(5H, m), 7.31 (2H, t, J=7.3 Hz), 7.53 (1H, t, J=8.3 Hz), 7.63 (1H,
t, J=8.8 Hz), 8.08 (1H, d, J=8.3 Hz), 8.20 (1H, d, J=8.3 Hz),
8.27-8.32 (2H, m), 8.37 (2H, d, J=6.4 Hz), 8.64 (1H, d, J=6.4 Hz),
8.67 (1H, d, J=6.4 Hz), 9.29 (1H, s), 9.34 (1H, s)
EXAMPLE 22
The same procedure as described in Example 19 was repeated except
that 300 mg of p-toluenesulfonyl chloride as a sulfonating agent,
700 mg of the amorphous compound obtained in Example 13, 10 ml of
pyridine as an eluate and chloroform/methanol (100:1) were used, to
obtain 812 mg of
1-[N-(5-isoquinolinesulfonyl)-N-methyl-p-(p-toluenesulfonylamino)phenylala
nyl]-4-phenylpiperazine.
IR (KBr) cm.sup.-1 : 1635, 1595, 1440, 1325, 1220, 1150;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.32 (3H, s), 2.50 (1H, dd,
J=4.9, 12.7 Hz), 2.68 (1H, m), 2.90-3.03 (4H, m), 3.10 (3H, s),
3.29 (1H, m), 3.42-3.73 (3H, m), 5.12 (1H, dd, J=5.4, 9.8 Hz),
6.79-6.97 (7H, m), 7.17 (2H, d, J=8.3 Hz), 7.28 (2H, t, J=7.3 Hz),
7.61 (2H, d, J=8.3 Hz), 7.69 (1H, t, J=7.8 Hz), 8.21 (1H, d, J=8.3
Hz), 8.31 (1H, dd, J=1.5, 7.3 Hz), 8.40 (1H, d, J=5.9 Hz), 8.65
(1H, d, J=6.4 Hz), 9.35 (1H, s).
EXAMPLE 23
1-{
N-(5-Isoquinolinesulfonyl)-P-[N'-(5-Isoquinolinesulfonyl)-N'-Methylamino]-
N-Methylphenylalanyl}-4-Phenylpiperazine
306 mg of the product in Example 21 was dissolved in 5 ml of
dimethylformamide, and to the solution were added 25 mg of 60%
sodium hydride and 0.1 ml of hydrogen iodide with ice cooling, and
the mixture was stirred for one hour with ice cooling. After the
addition of 30 ml of saturated sodium chloride, the mixture was
extracted with 30 ml of ethyl acetate, and the extract was washed
with saturated sodium chloride aqueous solution, dried over
magnesium sulfate and concentrated under a reduced pressure. The
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (80:1) to obtain 266 mg of the title
compound.
IR (KBr) cm.sup.-1 : 1640, 1600, 1445, 1340, 1225, 1150, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.41-2.61 (2H, m),
2.83-3.09 (3H, m), 3.07 (6H, s), 3.27 (1H, dd, J=10.7, 13.2 Hz),
3.43 (1H, m), 3.56-3.71 (3H, m) 5.18 (1H, dd, J=4.4, 10.7 Hz),
6.80-6.91 (3H, m), 6.94 (2H, d, J=8.8 Hz), 7.00 (2H, d, J=8.8 Hz),
7.21-7.30 (2H, m), 7.60 (1H, t, J=7.8 Hz), 7.73 (1H, t, J=7.8 Hz),
7.98 (1H, d, J=5.9 Hz), 8.14-8.23 (3H, m), 8.36 (1H, d, J=8.4 Hz),
8.40 (1H, d, J=5.9 Hz), 8.46 (1H, d, J=6.4 Hz), 8.69 (1H, d, J=6.4
Hz), 9.29 (1H, s), 9.37 (1H, s).
EXAMPLE 24
The same procedure as described in Example 23 was repeated except
that 594 mg of the product of Example 19 was dissolved in 6 ml of
dimethylformamide and to the solution were added 60 mg of 60%
sodium hydride and 0.1 ml of methyl iodide, to obtain 450 mg of
1-[N-(5-isoquinolinesulfonyl)-p-(N'-methanesulfonyl-N'-methylamino)
N-methylphenylalanyl]-4-phenylpiperazine.
IR (KBr) cm.sup.-1 : 1635, 1595, 1445, 1335, 1225, 1150, 1140;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.36 (1H, m), 2.50 (1H, dd,
J=3.9, 12.2 Hz), 2.64 (3H, s), 2.81 (1H, m), 2.96-3.16 (2H, m),
3.11 (3H, s), 3.16 (3H, s), 3.31 (1H, dd, J=10.7, 12.7 Hz),
3.37-3.62 (3H, m), 3.78 (1H, m), 5.20 (1H, dd, J=4.4, 10.7 Hz),
6.80 (2H, d, J=7.8 Hz), 6.88 (1H, t, J=7.3 Hz), 7.12 (2H, d, J=8.8
Hz), 7.21-7.31 (4H, m), 7.74 (1H, t, J=7.8 Hz), 8.24 (1H, d, J=7.8
Hz), 8.38 (1H, dd, J=1.0, 7.3 Hz), 8.47 (1H, d, J=6.4 Hz), 8.71
(1H, d, J=6.4 Hz), 9.37 (1H, s).
EXAMPLE 25
The same procedure as described in Example 23 was repeated, except
that 587 mg of the product of Example 20 was dissolved in 6 ml of
dimethylformamide and to the solution were added 50 mg of 60%
sodium hydride and 0.1 ml of methyl iodide, and elution was carried
out using chloroform/methanol (100:1), to obtain 490 mg of
1-{N-(5-isoquinolinesulfonyl)-N-methyl-p-[N'-methyl-N'-(1-naphtharenesulfo
nyl)amino]phenylalanyl}-4-phenylpiperazine.
IR (KBr) cm.sup.-1 : 1640, 1600, 1440, 1330, 1220, 1150, 1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.47 (1H, dd, J=4.4, 12.7
Hz), 2.53 (1H, m), 2.80-3.07 (3H, m), 3.07 (3H, s), 3.08 (3H, s),
3.27 (1H, dd, J=10.3, 12.7 Hz), 3.38 (1H, m), 3.51-3.65 (3H, m),
5.17 (1H, dd, J=4.4, 10.3 Hz), 6.81 (2H, d, J=8.8 Hz), 6.88 (1H, t,
J=7.3 Hz), 6.98 (4H, s), 7.24 (2H, dd, J=7.3, 8.8Hz), 7.38-7.57
(3H, m), 7.72 (1H, d, J=7.3 Hz), 7.88 (1H, d, J=7.8 Hz), 8.01 (1H,
d, J=8.3 Hz), 8.04 (1H, d, J=7.3 Hz), 8.23 (1H, d, J=8.3 Hz),
8.32-8.37 (2H, m), 8.46 (1H, d, J=5.9 Hz), 8.68 (1H, d, J=6.3 Hz),
9.36 (1H, s).
EXAMPLE 26
The same procedure as described in Example 23 was repeated, except
that 650 mg of the product of Example 22 was dissolved in 10 ml of
dimethylformamide, and to the solution were added 60 mg of 60%
sodium hydride and 0.1 ml of methyl iodide, and elution was carried
out using chloroform/methanol (100:1) , to obtain 603 mg of
1-{N-(5-isoquinolinesulfonyl)-N-methyl-p-[N'-methyl-N'-(p-toluenesulfonyl)
amino]phenylalanyl}-4-phenylpiperazine.
IR (KBr) cm.sup.-1 : 1640, 1600, 1440, 1335, 1220, 1145;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.37 (3H, s), 2.52 (1H, dd,
J=4.9, 12.7 Hz), 2.55 (1H, m), 2.80-3.10 (3H, m), 2.99 (3H, s),
3.11 (3H, s), 3.28 (1H, dd, J=10.3, 12.7 Hz), 3.40 (1H, m),
3.50-3.68 (3H, m), 5.20 (1H, dd, J=4.9, 10.3 Hz), 6.81 (2H, d,
J=8.3 Hz), 6.88 (1H, t, J=7.3 Hz), 6.98 (2H, d, J=8.8 Hz) 7.05 (2H,
d, J=8.8 Hz), 7.18 (2H, d, J=8.3 Hz), 7.24 (2H, dd, J=7.3, 8.3 Hz),
7.37 (2H, d, J=8.3 Hz), 7.73 (1H, t, J=7.8 Hz), 8.23 (1H, d, J=8.3
Hz), 8.36 (1H, dd, J=1.0, 7.8 Hz), 8.46 (1H, d, J=6.4 Hz), 8.70
(1H, d, J=6.4 Hz) 9.36 (1H, s).
REFERENCE EXAMPLE 11
1-(N-Benzyloxycarbonyltyrosyl)-4-(Tert-Butoxycarbonyl)Picerazine
21.31 g of N-benzyloxycarbonyltyrosine and 11.79 of
N-(tert-butoxycarbonyl)piperazine were dissolved in a mixed solvent
of 200 ml of methylene chloride and 100 ml of ethyl acetate, and to
the solution was added 14 g of DCC. After stirring at a room
temperature for 40 hours, precipitated insoluble matter was
filtered off, and the filtrate was concentrated under a reduced
pressure, and resulting residue was applied to a silica gel column
and eluted with hexane/ethyl acetate (1:1) to obtain 23.9 g of the
title compound in a colorless amorphous form
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.45 (9H, s), 2.80-3.02
(4H, m), 3.14-3.39 (4H, m), 3.49 (2H, m), 4.83 (1H, m), 5.08 (1H,
d, J=12 Hz), 5.10 (1H, d, J=12 Hz), 5.69 (1H, d, J=8.8 Hz), 6.17
(1H, br), 6.72 (2H, d, J=8.8 Hz), 7.01 (2H, d, J=8.3 Hz), 7.34 (5H,
s).
EXAMPLE 27
1-[N,O-Bis(5-Isoquinolinesulfonyl)Tyrosyl]-4-(Tert-Butoxycarbonyl)Piperazin
e
1.00 g of the amorphous compound obtained in Reference Example 11
was dissolved in 20 ml of methanol, to the solution was added 500
mg of 5% palladium on carbon, and the mixture was stirred under a
hydrogen atmosphere at a room temperature for 5 hours. After
removing insoluble matter by filtration, the filtrate was
concentrated under a reduced pressure. To the resulting residue
were added sequentially 30 ml of tetrahydrofuran, 630 mg of
5-isoquinolinesulfonyl chloride.HCl and 1.4 ml of triethylamine,
and the mixture was stirred at a room temperature for 50 hours, and
after the addition of 100 ml of water, extracted twice with 50 ml
of chloroform. The extract was dried over magnesium sulfate and
concentrated under a reduced pressure. The resulting residue was
then applied to a silica gel column and eluted with
chloroform/methanol (50:1 to 25:1) to obtain 1.38 g of the title
compound in a yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.45 (9H, s), 2.53-3.18
(10H, m), 4.29 (1H, m), 6.05 (1H, d, J=9.3 Hz), 6.61 (2H, d, J=8.8
Hz), 6.85 (2H, d, J=8.8 Hz), 7.62 (1H, t, J=7.8 Hz), 7.66 (1H, t,
J=7.8 Hz), 8.19 (2H, d, J=7.8 Hz), 8.26-8.31 (3H, m), 8.52 (1H, d,
J=5.9 Hz), 8.69 (1H, d, J=5.9 Hz), 8.84 (1H, d, J=6.4 Hz), 9.33
(1H, s), 9.43 (1H, s)
EXAMPLE 28
1-[N,O-Bis(5-Isoquinolinesulfonyl)Tyrosyl]Piperazine
366 mg of the amorphous compound prepared in Example 27 was
dissolved in 3 ml of chloroform, and to the solution was added 5 ml
of 3N hydrochloric acid/ethyl acetate. After stirring at a room
temperature for one hour, the mixture was concentrated under a
reduced pressure, and to resulting residue was added 50 ml of
saturated sodium bicarbonate aqueous solution. The mixture was then
twice extracted with 30 ml of a mixed solvent of
chloroform/methanol (5:1), and the extract was dried over magnesium
sulfate and concentrated under a reduced pressure to obtain 301 mg
of a crude preparation of the title compound in a colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.11 (1H, m), 2.35 (1H, m),
2.43 (2H, m), 2.70-2.83 (4H, m), 2.90 (1H, m), 3.09 (1H, m), 4.30
(1H, t, J=7.4 Hz), 6.65 (2H, d, J=8.3 Hz), 6.88 (2H, d, J=8.3 Hz),
7.62 (1H, dd, J=7.3, 8.3 Hz), 7.64 (1H, t, J=7.8 Hz), 8.17 (1H, d,
J=8.3 Hz), 8.24-8.31 (4H, m), 8.52 (1H, d, J=5.9 Hz), 8.68 (1H, d,
J=6.3 Hz), 8.83 (1H, d, J=6.4 Hz), 9.32 (1H, s), 9.43 (1H, s).
EXAMPLE 29
1-Benzyloxycarbonyl-4-[N-(5-Isoquinolinesulfonyl)Tyrosyl]Piperazine
620 mg of the crude product obtained in Example 28 was dissolved in
10 ml of methylene chloride, and to the solution were sequentially
added 0.29 ml of benzyloxycarbonyl chloride and 3.04 ml of
triethylamine with ice cooling. After stirring for two hours with
ice cooling, 40 ml of saturated sodium chloride aqueous solution
was added to the reaction mixture, which was then extracted twice
with 20 ml of chloroform, and the extract was dried over magnesium
sulfate and concentrated under a reduced pressure to obtain a
residue. The residue was dissolved in 6 ml of methanol, and after
the addition of 2 ml of 1N sodium hydroxide aqueous solution, the
mixture was refluxed for two hours, dried over magnesium sulfate
and concentrated under a reduced pressure. The resulting residue
was applied to a silica gel column and eluted with
chloroform/methanol (80:1 to 50:1) to obtain 336 mg of the title
compound as colorless crystals.
Melting point: 137.degree.-141.degree. C.
IR (KBr) cm.sup.-1 : 1700, 1630, 1510, 1417, 1318, 1218, 1148,
1128;
.sup.1 H-NMR(CDCl.sub.3 -CD.sub.3 OD, .delta. ppm): 2.60-2.77 (2H,
m), 2.80-3.55 (8H, m), 4.25 (1H, t, J=7.8 Hz), 5.10 (1H, s), 5.12
(1H, s), 6.29, 6.74 (Total 2H, each d, each J=8.3 Hz), 6.60, 7.01
(Total 2H, each d, each J=8.3 Hz), 7.35 (5H, s), 7.60 (1H, t, J=7.8
Hz), 8.15 (1H, d, J=8.3 Hz), 8.26 (1H, d, J=7.8 Hz), 8.29 (1H, d,
J=5.9 Hz), 8.57 (1H, d, J=5.9 Hz), 9.25 (1H, s).
EXAMPLE 30
The same procedure as described in Example 29 was repeated to
obtain
1-[N-(5-isoquinolinesulfonyl)tyrosyl]-4-phenylacetylpiperazine in a
yellow amorphous form.
IR (KBr) cm.sup.-1 : 1620, 1510, 1435, 1320, 1228, 1152, 1130;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.20-3.45 (10H, m), 3.67,
370 (Total 2H, each s), 4.32, 4.82 (Total 1H, each m), 6.45, 6.65
(Total 2H, each d, each J=8.3 Hz), 6.82, 7.00 (Total 2H, each d,
each J=8.3 Hz), 7.13-7.39 (5H, m), 7.60-7.74 (1H, m), 8.13-8.42
(3H, m), 8.64 (1H, d, J=5.9 Hz), 9.18 (1H, br), 9.39 (1H, br).
EXAMPLE 31
The same procedure as described in Example 29 was repeated to
obtain
1-[N-(5-isoquinolinesulfonyl)tyrosyl]-4-(3-phenylpropionyl)piperazine
as colorless crystals.
Melting point: 172.degree.-178.degree. C.;
IR (KBr) cm.sup.-1 : 1630, 1510, 1440, 1320, 1225, 1150, 1128;
.sup.1 H-NMR (CDCl.sub.3 -CD.sub.3 OD, .delta. ppm): 2.50-3.47
(14H, m), 4.26 (1H, t, J=7.3 Hz), 6.32 (2H, d, J=8.3 Hz), 6.62 (2H,
d, J=8.3 Hz), 7.15-7.34 (5H, m), 7.62 (1H, t, J=7.8 Hz), 8.17 (1H,
d, J=7.8 Hz), 8.24-8.33 (2H, m), 8.58 (1H, d, J=5.4 Hz), 9.26 (1H,
s).
EXAMPLE 32
1-[N,O-Bis(5-Isoquinolinesulphonyl)Tyrosyl]-4-(3-Phenylpropyl)Piperazine
301 mg of the crude product obtained in Example 28 and 95 mg of
3-phenylpropyl bromide were dissolved in 5 ml of dimethylformamide,
and to the solution were added 66 mg of potassium carbonate and 72
mg of sodium iodide. After stirring at 80.degree. C. for 7 hours,
30 ml of saturated sodium chloride was added to the reaction
mixture, which was then extracted with 40 ml of ethyl acetate, and
the extract was washed with 30 ml of saturated sodium chloride
aqueous solution, dried over magnesium sulfate, and concentrated
under a reduced pressure. The resulting residue was applied to a
silica gel column and eluted with chloroform/methanol (40:1) to
obtain 216 mg of the title compound in a yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.60-1.95 (6H, m),
2.06-2.29 (2H, m), 2.53-3.20 (8H, m), 4.28 (1H, m), 5.98 (1H, d,
J=9.3 Hz), 6.64 (2H, d, J=8.3 Hz), 6.86 (2H, d, J=8.3 Hz),
7.14-7.35 (5H, m), 7.59 (1H, t, J=7.8 Hz), 7.62 (1H, t, J=7.8 Hz),
8.12 (1H, d, J=8.3 Hz), 8.23-8.29 (4H, m), 8.52 (1H, d, J=5.9 Hz),
8.68 (1H, d, J=6.4 Hz), 8.82 (1H, d, J=6.4 Hz), 9.28 (1H, s), 9.42
(1H, s).
EXAMPLE 33
1-[N-(5-Isoquinolinesulfonyl)Tyrosyl]-4-(3-Phenylpropyl)Piperazine
216 mg of the amorphous compound obtained in Example 32 was
dissolved in 3 ml of methanol, and to the solution was added 0.6 ml
of 2N potassium hydroxide aqueous solution. The mixture was
refluxed for 10 hours, and after the addition of 30 ml of saturated
sodium chloride aqueous solution, extracted twice with 20 ml of a
mixed solvent of chloroform/isopropanol (5:1). The extract was
dried over magnesium sulfate and concentrated under a reduced
pressure, and a resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (40:1 to 10:1) to obtain
74 mg of the title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1630, 1510, 1440, 1320, 1230, 1150, 1128;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.65-1.83 (2H, m),
2.00-2.37 (6H, m), 2.57-2.80 (4H, m), 3.02-3.42 (4H, m), 4.31 (1H,
m), 6.30 (2H, d, J=8.3 Hz), 6.41 (1H, d, J=9.3 Hz), 6.65 (2H, d,
J=8.3 Hz), 7.15-7.37 (5H, m), 7.60 (1H, t, J=7.8 Hz), 8.16 (1H, d,
J=8.3 Hz), 8.23-8.33 (2H, m), 8.58 (1H, br), 9.33 (1H, br).
REFERENCE EXAMPLE 12
1-[N-(Tert-Butoxycarbonyl)Tyrosyl]-4-Phenylpiperazine
19.7 g of N-(tert-butoxycarbonyl)tyrosine, 12.5 g of
N-phenylpiperazine and 16.1 g of N-hydroxybenzotriazole were
dissolved in 100 ml of tetrahydrofuran, and to the solution was
added dropwise a solution of 18.7 g of DCC in 50 ml of
tetrahydrofuran for 20 minutes with ice cooling, and the mixture
was stirred for one hour. The reaction mixture was filtered to
remove insoluble matter, which was then washed with 300 ml of ethyl
acetate, and the filtrates were combined and concentrated under a
reduced pressure. The resulting residue was dissolved in 500 ml of
ethyl acetate, and the solution was washed three times with
saturated sodium bicarbonate aqueous solution and once with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate, and concentrated under a reduced pressure. The resulting
residue was applied to a silica gel column and eluted with ethyl
acetate/hexane (1:2 to 1:1) to collect desired fractions, which
were then combined and concentrated under a reduced pressure.
Resulting residue was dissolved in 100 ml of ethyl acetate, and the
solution was allowed to stand overnight in a refrigerator and then
filtered to remove insoluble matter. The filtrate was concentrated
under a reduced pressure, subjected to azeatropic distillation with
benzene and dried under a reduced pressure to obtain 40.0 g of the
title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1700, 1620, 1220;
.sup.1 H-NMR (DMSO.d.sub.6, .delta. ppm): 1.33 (9H, s), 2.6-3.1
(6H, m), 3.4-3.7 (4H, m), 4.55 (1H, m), 6.64 (2H, d, J=8.2 Hz),
6.80 (1H, t, J=7.3 Hz), 6.90 (2H, d, J=7.9 Hz), 7.02 (2H, d, J=8.2
Hz), 7.22 (2H, dd, J=7.3, 7.9 Hz), 9.16 (1H, s).
REFERENCE EXAMPLE 13
1-[2-(Tert-Butoxycarbonylamino)-3-(P-Hydroxyphenyl)Propyl]-4-Phenylpiperazi
ne
With ice cooling, to a solution of 8.0 g of lithium aluminum
hydride in 230 ml of tetrahydrofuran a solution of 28.0 g of
aluminum chloride in 230 ml of ether was added dropwise for 50
minutes, and after 15 minutes to the resulting solution was added
dropwise a solution of 40.0 g of the amorphous compound obtained in
Reference Example 12 in 230 ml of tetrahydrofuran, for 15 minutes.
The reaction mixture was allowed to become a room temperature, and
after the addition of 300 ml of tetrahydrofuran, stirred for 25
minutes. The mixture was filtered to remove insoluble matter which
was then washed with tetrahydrofuran. The combined filtrate was
concentrated under a reduced pressure, and resulting residue was
applied to a silica gel column, and eluted with chloroform/methanol
(20:1) to collect fractions, which were then concentrated under a
reduced pressure. Then 100 ml of ethyl acetate was added to the
residue to crystallize a product. The product was filtered to
collect, and washed 5 times with a mother liquid and further 3
times with n-hexane and dried under a reduced pressure to obtain
24.1 g of the title compound as colorless crystals.
Melting point: 199.degree.-202.degree. C. (decomposed).
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 1.33 (9H, s), 2.2-2.8
(8H, m), 3.09 (4H, brs), 3.72 (1H, m), 6.5-7.0 (7H, m), 7.20 (2H,
t, J=8.3 Hz), 9.10 (1H, s);
IR (KBr) cm.sup.-1 : 1690, 1500, 1230.
REFERENCE EXAMPLE 14
1-[2-Amino-3-(P-Hydroxyphenyl)Propyl]-4-Phenylpiperazine
To a suspension of 23.6 g of the crystals obtained in Reference
Example 13 in 100 ml of ethyl acetate, was added dropwise 215 ml of
4N hydrochloric acid solution in ethyl acetate for 30 minutes, and
after stirring for 90 minutes, excess hydrochloric acid was removed
from the reaction mixture under a reduced pressure. After
extraction with 200 ml of water, the separated ethyl acetate layer
was extracted with 50 ml of 1N hydrochloric acid aqueous solution.
The aqueous layers were combined and neutralized to pH 7.4 with
solid sodium bicarbonate, and resulting crystals was collected,
washed with water and benzene and dried by phosphorus pentaoxide in
a desiccator under a reduced pressure to obtain 16.9 g of the title
compound as colorless crystals.
Melting point: >270.degree. C.;
IR (KBr) cm.sup.-1 : 1600, 1470, 1230;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.2-3.5 (13H, m), 6.7-6.8
(3H, m), 6.90 (2H, d, J=8.3 Hz), 7.07 (2H, d, J=8.3 Hz), 7.19 (2H,
t, J=7.6 Hz), 8.00 (2H, brs), 9.41 (1H, brs).
EXAMPLE 34
N-{1-[p-(5-Isoquinolinesulfonyloxy)Benzyl-2-(4-Phenylpiperazinyl)Ethyl}-5-I
soquinolinesulfonamide
To a suspension of 22.96 g of the crystals obtained in Reference
Example 14 in 700 ml of tetrahydrofuran, was added 51.01 g of
5-isoquinolinesulfonyl chloride.HCl with ice cooling for 5 minutes,
and then was added dropwise 103 ml of triethylamine for 30 minutes.
After allowing to warm to a room temperature, the reaction mixture
was poured into 460 ml of ice water, and the whole was extracted
with 920 ml and 230 ml of chloroform. The combined extract was
washed with saturated sodium chloride aqueous solution, dried over
magnesium sulfate and concentrated to dryness under a reduced
pressure. The resulting amorphous residue was applied to a silica
gel column and eluted with chloroform/methanol (100:1 to 50:1) to
obtain 45.5 g of the title compound in a yellow amorphous form.
IR (KBr) cm.sup.-1 : 1600, 1500, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.0-3.0 (12H, m), 3.30 (1H,
m), 5.51 (1H, brs), 6.7-7.8 (11H, m), 8.20 (1H, d, J=8.2 Hz), 8.28
(2H, d, J=7.7 Hz), 8.4-8.5 (2H, m), 8.53 (1H, d, J=6.1 Hz), 8.67
(1H, d, J=6.1 Hz) 8.81 (1H, d, J=6.1 Hz), 9.35 (1H, s), 9.42 (1H,
s).
EXAMPLE 35
N-{(1-[p-(5-Isoquinolinesulfonyloxy)Benzyl]-2-(4-Phenylpiperazinyl)Ethyl}-N
-Methyl-5-Isoquinolinesulfonamide
To a solution of 25.0 g of the amorphous compound obtained in
Example 34 in 200 ml of dimethylformamide was added in three
portions 1.64 g of 60% sodium hydride, and after 5 minutes, also
was added dropwise 3.14 ml of methyl iodide for two minutes, and
the reaction mixture was stirred for one hour. The reaction mixture
was poured to 400 ml of ice water, and the whole was extracted with
200 ml, 200 ml and 100 ml of ethyl acetate. The combined extract
was washed three times with saturated sodium chloride aqueous
solution, dried over magnesium sulfate and concentrated under a
reduced pressure, and the resulting residue was applied to a silica
gel column and eluted with chloroform/methanol (100:1) to obtain
20.0 g of the title compound in a yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.30 (1H, dd, J=6.8, 12.2
Hz), 2.39-2.52 (5H, m), 2.68 (1H, dd, J=7.3, 14.2 Hz), 2.86 (3H,
s), 2.89-3.01 (5H, m), 4.18 (1H, m), 6.61 (2H, d, J=8.3 Hz),
6.83-6.92 (5H, m), 7.26 (2H, t, J=7.8 Hz), 7.57 (1H, t, J=7.8 Hz),
7.60 (1H, t, J=7.8 Hz), 8.10 (1H, d, J=8.3 Hz), 8.23-8.28 (3H, m),
8.33 (1H, dd, J=1.0, 7.3 Hz), 8.56 (1H, d, J=5.9 Hz), 8.58 (1H, d,
J=5.9 Hz), 8.83 (1H, d, J=5.9 Hz), 9.27 (1H, s), 9.41 (1H, d, J=1.0
Hz)
IR (KBr) cm.sup.-1 : 1620, 1500 1370 1325, 1130.
EXAMPLE 36
N-[1-(P-Hydroxybenzyl)-2-(4-Phenylpiperazinyl)Ethyl]-N-Methyl-5-Isoquinolin
esulfonamide
To 17.7 g of the amorphous compound obtained in Example 35 were
added 240 ml of methanol, 60 ml of tetrahydrofuran and 29 ml of 2N
sodium hydroxide aqueous solution, and the mixture was refluxed for
150 minutes, and then poured to saturated sodium chloride aqueous
solution. The mixture was extracted three times with 200 ml of
chloroform, and the extract was washed with saturated sodium
chloride aqueous solution, dried over magnesium sulfate, and
concentrated under a reduced pressure. The resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(50:1), and 10.9 g of a yellow amorphous product was obtained from
the elute. To the product was added 54 ml of ethanol and the
mixture was stirred at a room temperature for one hour, and under
ice cooling for 30 minutes to form crystals, which was then
collected, washed three times with a mother liquid and twice with
benzene, and dried under a reduced pressure to obtain 8.2 g of the
title compound as light yellow crystals.
Melting point: 201.degree. C.;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.49 (1H, dd, J=6.8, 9.8
Hz), 2.52-2.77 (7H, m), 2.95 (1H, dd, J=4.4, 14.2 Hz), 3.02 (3H,
s), 3.14 (4H, t, J=4.9 Hz), 4.03 (1H, m), 6.26 (2H, d, J=8.3 Hz),
6.61 (2H, d, J=8.8 Hz), 6.86 (1H, t, J=6.8 Hz), 6.91 (2H, d, J=7.3
Hz), 7.27 (2H, t, J=7.8 Hz), 7.60 (1H, t, J=7.3 Hz), 8.11 (1H, d,
J=5.9 Hz), 8.14 (1H, d, J=6.4 Hz), 8.33 (1H, dd, J=1.0, 7.3 Hz),
8.47 (1H, d, J=6.3 Hz), 9.27 (1H, s);
IR (KBr) cm.sup.-1 : 1600, 1510, 1445, 1320, 1205, 1150, 1125.
EXAMPLE 37
The amorphous compound obtained in Example 34 was subjected to
alkaline hydrolysis according to the procedure as described in
Example 36, to obtain
N-[1-(p-hydroxybenzyl)-2-(4-phenylpiperazinyl)ethyl]-5-isoquinoline
sulfonamide in a colorless amorphous.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.25-2.55 (6H, m), 2.65
(1H, dd, J=13.7, 6.85 Hz), 2.79 (1H, dd, J=13.7, 6.85 Hz), 2.82-3.0
(4H, m), 3.37 (1H, quintet, J=6.85 Hz), 6.42 (2H, d, J=8.57 Hz),
6.69 (2H, d, J=8.57 Hz), 6.84 (2H, d, J=8.57 Hz), 6.85 (1H, t,
J=8.57 Hz), 7.26 (2H, t, J=8.57 Hz), 7.69 (1H, t, J=7.42 Hz), 8.22
(1H, d, J=7.99 Hz), 8.38 (1H, d, J=6.28 Hz), 8.43 (1H, dd, J=7.42,
1.0 Hz), 8.59 (1H, d, J=6.28 Hz), 9.34 (1H, d, J=1.0 Hz).
EXAMPLE 38
N-[1-(P-Methoxybenzyl)-2-(4-Phenylpiperazinyl)Ethyl]-N-Methyl-5-Isoquinolin
esulfonamide
1.51 g of the crystals obtained in Example 36 was dissolved in 20
ml of a mixed solvent of dimethylformamide/tetrahydrofuran (1:1),
and to the solution was added 140 mg of 60% sodium hydride with
stirring under ice cooling, and stirring was continued for about 30
minutes. After foaming was finished, 490 mg of methyl iodide was
added and the mixture was further stirred overnight at a room
temperature. After the addition of ice, the reaction mixture was
three times extracted with 50 ml of ethyl acetate, and the extract
was washed with saturated sodium chloride aqueous solution, dried
over magnesium sulfate and concentrated under a reduced pressure.
The resulting residue was applied to a silicon gel column and
eluted with chloroform/methanol (100:1) to obtain 1.55 g of the
title compound as a light brown oil.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.45 (1H, dd, J=7.1, 13.8
Hz), 2.6 (5H, m), 2.65 (1H, m), 2.88 (1H, s), 2.95 (3H, s), 3.05
(4H, m), 3.74 (3H, s), 4.2 (1H, m), 6.5 (2H, d, J=8.5 Hz), 6.9 (5H,
m), 7.25 (2H, m), 7.55 (1H, t, J=7.5 Hz), 8.07 (1H, d, J=7.5 Hz),
8.22 (1H, d, J=6.4 Hz), 8.56 (1H, d, J=6.4 Hz), 9.22 (1H, s);
IR (KBr) cm.sup.-1 : 1600, 1510, 1320, 1240, 1150, 1130.
EXAMPLE 39
The same procedures as described in Reference Examples 12 to 14 and
Example 34 were repeated except that 1-(2-pyrimidyl)piperazine.
dihydrochloride was used in place of N-phenylpiperazine, to obtain
N-{1-[p-(5-isoquinolinesufonyloxy)benzyl]-2-[4-(2-pyrimidyl)piperazinyl]et
hyl}-5-isoquinolinesulfonamide in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8-1.96 (2H, m), 1.96-2.24
(4H, m), 2.8 (1H, dd, J=13.7, 6.85 Hz), 2.92 (1H, dd, J=13.7, 4.57
Hz), 3.0-3.47 (5H, m), 5.49 (1H, br), 6.47 (1H, t, J=4.57 Hz), 6.70
(2H, d, J=8.57 Hz), 6.94 (2H, d, J=8.57 Hz), 7.64 (1H, t, J=7.42
Hz), 7.70 (1H, t, J=7.42 Hz), 8.17-8.35 (5H, m), 8.37-8.48 (2H, m)
8.52 (1H, d, J=5.71 Hz), 8.68 (1H, d, J=6.28 Hz), 8.82 (1H, d,
J=6.28 Hz) 9.37 (1H, s), 9.42 (1H, d, J=1.0 Hz).
EXAMPLE 40
The amorphous compound of the Example 39 was treated as described
in Example 37, to obtain
N-{1-(p-hydroxybenzyl)-2-[4-(2-pyrimidyl)piperazinyl]ethyl}-5-isoquinoline
sulfonamide in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.05-2.55 (6H, m), 2.66
(1H, dd, J=13.13, 6.85 Hz), 2.82 (1H, dd, J=13.13, 6.28 Hz),
3.2-3.7 (5H, m), 6.42 (2H, d, J=7.99 Hz), 6.46 (1H, t, J=4.57 Hz),
6.72 (2H, d, J=7.99 Hz), 7.68 (1H, t, J=7.42 Hz), 8.20 (1H, d,
J=8.57 Hz), 8.27 (2H, d, J=4.57 Hz), 8.35-8.50 (2H, m), 8.57 (1H,
d, J=5.71 Hz), 9.31 (1H, s)
EXAMPLE 41
The amorphous compound of Example 39 was treated as described in
Example 35, to obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(2-pyrimidyl)piperazinyl]e
thyl}-N-methyl-5-isoquinolinesulfonamide in a colorless amorphous
form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.15-2.36 (5H, m), 2.44
(1H, dd, J=13.7, 6.85 Hz), 2.71 (1H, dd, J=13.13, 6.85 Hz),
2.8-2.95 (1H, m), 2.87 (3H, s), 3.56 (4H, m), 4.17 (1H, quintet,
J=6.85 Hz), 6.48 (1H, t, J=4.85 Hz), 6.63 (2H, d, J=9.14 Hz), 6.92
(2H, d, J=9.14 Hz), 7.58 (1H, t, J=6.85 Hz), 7.61 (1H, t, J=6.85
Hz), 8.13 (1H, d, J=7.42 Hz), 8.18-8.38 (6H, m), 8.56 (1H, d,
J=6.28 Hz), 8.58 (1H, d, J=6.28 Hz), 8.84 (1H, d, J=6.28 Hz), 9.28
(1H, s), 9.42 (1H, d, J=1.0 Hz)
EXAMPLE 42
The amorphous compound of Example 41 was treated as described in
Example 36, to obtain
N-{1-(p-hydroxybenzyl)-2-[4-(2-pyrimidyl)piperazinyl]ethyl}-N-methyl-5-iso
quinolinesulfonamide in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1585, 1510, 1355, 1325, 1255, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.4-2.65 (6H, m), 2.70 (1H,
dd, J=13.13, 6.28 Hz), 2.97 (1H, dd, J=13.13, 5.71 Hz), 3.03 (3H,
s), 3.77 (4H, t, J=4.57 Hz), 4.04 (1H, m), 6.28 (2H, d, J=8.57 Hz),
6.49 (1H, t, J=5.14 Hz), 6.62 (2H, d, J=8.57 Hz), 7.62 (1H, t,
J=7.42 Hz), 8.11 (1H, d, J=6.28 Hz), 8.15 (1H, d, J=7.42 Hz), 8.30
(2H, d, J=5.14 Hz), 8.32 (1H, dd, J=7.42, 1.0 Hz), 8.48 (1H, d,
J=6.28 Hz), 9.28 (1H, s).
EXAMPLE 43
The same procedures as described in Reference Examples 12 to 14 and
Examples 34 and 35 were repeated except that
N-(tert-butoxycarbonyl)phenylalanine was used in place of
N-(tert-butoxycarbonyl) tyrosine, to obtain
N-[1-benzyl-2-(4-phenylpiperazinyl)ethyl]-N-methyl-5-isoquinolinesulfonami
de in a light yellow amorphous form.
IR (KBr) cm.sup.-1 : 1595, 1490, 1300, 1220, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.45 (1H, dd, J=6.6, 13
Hz), 2.7 (1H, dd, J=8, 13 Hz), 2.55 (5H, m), 3.0 (5H, m), 4.3 (1H,
m), 6.84, 6.9 (Total 3H, m), 7.0 (5H, brs), 7.25 (2H, m), 7.5 (1H,
t, J=7.5 Hz), 8.05 (1H, d, J=8 Hz), 8.2 (1H, d, J=7.5 Hz), 8.3 (1H,
d, J=8 Hz), 8.55 (1H, d, J=6.1 Hz), 9.23 (1H, s).
EXAMPLE 44
The same procedures as described in Reference Examples 12 to 14 and
Example 34 were repeated except that N-(2-pyridyl) piperazine was
used in place of N-phenylpiperazine, to obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl-2-[4-(2-pyridyl)piperazinyl]ethy
l}-5-isoquinolinesulfonamide in a yellow amorphous form
IR (KBr) cm.sup.-1 : 1615, 1590, 1480, 1430, 1370, 1310, 1150,
1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.93-2.21 (6H, m), 2.77
(1H, dd, J=7.3, 14.2 Hz), 2.83-3.00 (3H, m), 3.02-3.19 (2H, m),
3.29 (1H, m), 5.46 (1H, br), 6.47 (1H, d, J=8.8 Hz), 6.62 (1H, dd,
J=4.9, 7.3 Hz), 6.69 (2H, d, J=8.8 Hz), 6.92 (2H, d, J=8.8 Hz),
7.44 (1H, ddd, J=1.0, 8.8, 7.3 Hz), 7.64 (1H, t, J=7.8 Hz), 7.70
(1H, dd, J=7.3, 8.3 Hz), 8.13 (1H, dd, J=1.0, 4.9 Hz), 8.22 (1H, d,
J=8.3 Hz), 8.28 (2H, d, J=7.3 Hz), 8.43 (2H, m), 8.53 (1H, d, J=5.9
Hz), 8.67 (1H, d, J=6.3 Hz), 8.81 (1H, d, J=5.9 Hz), 9.35 (1H, d,
J=1.0 Hz), 9.42 (1H, s).
EXAMPLE 45
The product of Example 44 was treated as described in Example 35 to
obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(2-pyridyl)piperazinyl]eth
yl}-N-methyl-5-isoquinolinesulfonamide
IR (KBr) cm.sup.-1 : 1590, 1480, 1430, 1370, 1310, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.23-2.50 (6H, m), 2.69
(1H, dd, J=7.3, 14.2 Hz), 2.86 (3H, s), 2.88 (1H, dd, J=14.2, 10.2
Hz), 3.30 (4H, m), 4.18 (1H, m), 6.55-6.65 (4H, m), 6.90 (2H, d,
J=8.8 Hz), 7.47 (1H, ddd, J=1.0, 7.3, 8.8 Hz), 7.58 (1H, dd, J=7.3,
8.3 Hz), 7.60 (1H, t, J=7.8 Hz), 8.11 (1H, d, J=8.3 Hz), 8.17 (1H,
dd, J=1.0, 4.9 Hz), 8.22-8.27 (3H, m), 8.33 (1H, dd, J=1.0, 7.3
Hz), 8.56 (1H, d, J=5.9 Hz), 8.58 (1H, d, J=5.9 Hz), 8.84 (1H, d,
J=6.4 Hz), 9.28 (1H, s), 9.41 (1H, s).
EXAMPLE 46
The product of Example 45 was treated as described in Example 36 to
obtain
N-{1-(p-hydroxybenzyl)-2-[4-(2-pyridyl)piperazinyl]ethyl}-N-methyl-5-isoqu
inolinesulfonamide.
IR (KBr) cm.sup.-1 : 1590, 1475, 1445, 1320, 1230, 1150, 1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.48 (1H, dd, J=3.4, 9.4
Hz), 2.50-2.75 (6H, m), 2.95 (1H, dd, J=4.9, 14.7 Hz), 3.02 (3H,
s), 3.49 (4H, t, J=4.9 Hz), 4.06 (1H, m), 6.27 (2H, d, J=8.3 Hz),
6.62 (2H, d, J=8.3 Hz), 6.61-6.66 (2H, m), 7.43 (1H, ddd, J=1.0,
7.3, 8.8 Hz), 7.61 (1H, dd, J=7.3, 8.3 Hz), 8.10-8.16 (2H, m), 8.19
(1H, dd, J=1.0, 4.3 Hz), 8.32 (1H, dd, J=1.0, 7.3 Hz), 8.48 (1H, d,
J=6.4 Hz), 9.28 (1H, s).
EXAMPLE 47
The same procedures as described in Reference Example 12 to 14 and
Examples 34 to 36 were repeated except that
N-(m-chlorophenyl)piperazine was used in place of
N-phenylpiperazine, to obtain
N-{2-[4-(m-chlorophenyl)piperazinyl]-1-(p-hydroxybenzyl)ethyl}-N-methyl-5-
isoquinolinesulfonamide in a light yellow amorphous form.
IR (KBr) cm.sup.-1 : 1590, 1320, 1230, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.5 (1H, dd, J=12.0, 10
Hz), 2.5-2.8 (2H, m), 2.6-2.7 (4H, m), 2.95 (1H, dd, J=4.5, 13.8
Hz), 3.0 (3H, s), 3.15 (4H, m), 4.0 (1H, m), 6.22 (2H, d, J=8.0
Hz), 6.55 (2H, d, J=8.0 Hz), 6.77 (1H, dd, J=8.5, 2.2 Hz), 6.8 (1H,
d, J=8.0 Hz), 6.85 (1H, d, J=2.2 Hz), 7.16 (1H, t, J=8.0 Hz), 7.6
(1H, t, J=7.8 Hz), 8.1 (1H, d, J=6.1 Hz), 8.15 (1H, d, J=8.1 Hz),
8.3 (1H, d, J=7.3 Hz), 8.45 (1H, d, J=6.4 Hz), 9.28 (1H, s).
EXAMPLE 48
The same procedures as described in Reference Examples 12 to 14 and
Example 34 were repeated except that N-(p-fluorophenyl)piperazine
was used in place of N-phenylpiperazine, to obtain
N-{2-[4-(p-fluorophenyl)piperazinyl]-1-[p-(5-isoquinolinesulfonyloxy)benzy
l]ethyl]}-5-isoquinolinesulfonamide in a colorless amorphous
form.
IR (KBr) cm.sup.-1 : 1610, 1500, 1370, 1320, 1210, 1130, 860,
820;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.0-2.3 (5H, m), 2.4-2.9
(6H, m), 3.3 (1H, m), 6.6-6.75 (4H, m), 6.85-7.0 (4H, m), 7.65 (1H,
t, J=8.1 Hz), 7.7 (1H, t, J=8.4 Hz), 8.2 (1H, d, J=8.3 Hz), 8.3
(1H, d, J=7.8 Hz), 8.4 (1H, d, J=6.3 Hz), 8.4 (1H, d, J=6.1 Hz),
8.5 (1H, d, J=6.1), 8.65 (1H, d, J=6.1 Hz), 8.8 (1H, d, J=6.3 Hz),
9.3 (1H, s), 9.4 (1H, s).
EXAMPLE 49
The amorphous compound obtained in Example 48 was methylated
according to the procedure described in Example 35 to obtain
N-{2-[4-(p-fluorophenyl)piperazinyl]-1-[p-(5-isoquinolinesulfonyloxy)benzy
l]ethyl]}-N-methyl-5-isoquinolinesulfonamide in a light yellow
amorphous form.
IR (KBr) cm.sup.-1 : 1620, 1510, 1370, 1330, 1210, 1140.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.3 (1H, dd, J=12.1, 6.5
Hz), 24.5 (4H, m), 2.4-2.6 (1H, m), 2.67 (1H, dd, J=13.8, 7.8 Hz),
2.75-3.0 (5H, m), 4.17 (1H, m), 6.63 (2H, d, J=8.6 Hz), 6.7-7.0
(6H, m), 7.57 (1H, t, J=8.0 Hz), 7.60 (1H, t, J=7.6 Hz), 8.1 (1H,
d, J=8.0 Hz), 8.2-8.35 (4H, m), 8.55 (1H, d, J=5.4 Hz), 8.56 (1H,
d, J=8.1 Hz), 8.83 (1H, d, J=6.3 Hz), 9.27 (1H, d, J=0.7 Hz), 9.40
(1H, d, J=1.0 Hz)
EXAMPLE 50
According to the procedure described in Example 36, 160 mg of the
amorphous compound obtained in Example 49 was dissolved in 2 ml of
methanol, and to the solution was added 0.5 ml of 2N sodium
hydroxide, and the reaction mixture was refluxed for two hours,
cooled, and extracted three times with chloroform. The extract was
purified on a silica gel column using chloroform/methanol (100:2),
to obtain 103 mg of
N-{1-(p-hydroxybenzyl)-2-[4-(p-fluorophenyl)piperazinyl]ethyl}-N-methyl-5-
isoquinolinesulfonamide in a light yellow amorphous form.
IR (KBr) cm.sup.-1 : 1610, 1500, 1320, 1230, 1150, 1130, 820;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.4-2.6 (2H, m), 2.6-2.8
(1H, m), 2.8-3.0 (1H, m), 2.75 (4H, m), 3.05 (1H, m), 3.1 (1H, m),
6.3 (2H, d, J=8.3 Hz), 6.67 (2H, d, J=8.3 Hz), 6.87 (2H, dd, J=8.3,
10.1 Hz), 6.95 (2H, t, J=8.3 Hz), 7.6 (1H, dd, J=7.6, 8.0 Hz), 8.12
(1H, d, J=9.0 Hz), 8.13 (1H, d, J=6.1 Hz), 8.3 (1H, d, J=7.3 Hz),
8.5 (1H, d, J=6.1 Hz), 9.25 (1H, s).
EXAMPLE 51
The same procedures as described in Reference Examples 12 to 14 and
Examples 34 to 36 were repeated except that
N-(m-methylphenyl)piperazine was used in place of
N-phenylpiperazine, to obtain
N-{1-(p-hydroxybenzyl)-2-[4-(m-methylphenyl)piperazinyl]ethyl}-N-methyl-5-
isoquinolinesulfonamide in a light yellow amorphous form.
IR (KBr) cm.sup.-1 : 1600, 1440, 1320, 1210, 1190, 1150, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.30 (3H, s), 2.55 (4H, m),
2.96 (1H, dd, J=11.6, 7.1 Hz), 2.5-2.9 (3H, m), 2.9 (3H, s), 3.1
(4H, m), 4.3 (1H, m), 6.8 (2H, d, J=8.3 Hz), 7.0 (2H, d, J=8.3 Hz),
7.0-7.15 (3H, m), 7.3 (1H, m), 7.55 (1H, t, J=7.8 Hz), 8.1 (1H, d,
J=7.8 Hz), 8.2-8.3 (2H, complex), 8.58 (1H, d, J=6.1 Hz), 9.25 (1H,
s).
EXAMPLE 52
The same procedures as described in reference Examples 12 to 14 and
Example 34 were sequentially repeated except that
N-(p-methoxyphenyl)piperazine was used in place of
N-phenylpiperazine, to obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl-2-[4-(p-methoxyphenyl)piperaziny
l]ethyl}-5-isoquinolinesulfonamide in yellow amorphous form.
IR (KBr) cm.sup.-1 : 1615, 1500, 1360, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.96-2.22 (6H, m),
2.39-2.52 (2H, m), 2.52-2.67 (2H, m), 2.77 (1H, dd, J=7.3, 14.2
Hz), 2.90 (1H, dd, J=4.4, 14.2 Hz), 3.27 (1H, m), 3.76 (3H, s),
5.50 (1H, br), 6.70 (4H, d, J=8.8 Hz), 6.82 (2H, d, J=8.8 Hz), 6.94
(2H, d, J=8.8 Hz), 7.65 (1H, t, J=7.8 Hz), 7.70 (1H, t, J=7.3 Hz),
8.21 (1H, d, J=8.3 Hz), 8.29 (2H, d, J=7.8 Hz), 8.40-8.43 (2H, m),
8.53 (1H, d, J=5.9 Hz), 8.68 (1H, d, J=6.4 Hz), 8.81 (1H, d, J=5.9
Hz), 9.36 (1H, s), 9.42 (1H, s).
EXAMPLE 53
The amorphous compound of Example 52 was treated with methyl iodide
according to the procedure described in Example 35 to obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(p-methoxyphenyl)piperazin
yl]ethyl}-N-methyl-5-isoquinolinesulfonamide in a yellow amorphous
form.
IR (KBr) cm.sup.-1 : 1665, 1615, 1505, 1365, 1320, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.30 (1H, dd, J=6.8, 12.2
Hz), 2.37-2.51 (5H, m), 2.68 (1H, dd, J=7.3, 14.2 Hz), 2.85 (3H,
s), 2.78-2.97 (5H, m), 3.77 (3H, s), 4.16 (1H, m), 6.62 (2H, d,
J=8.3 Hz), 6.82 (4H, s), 6.90 (2H, d, J=8.3 Hz), 7.57 (1H, t, J=7.8
Hz), 7.60 (1H, t, J=7.8 Hz), 8.11 (1H, d, J=8.3 Hz), 8.23-8.28 (3H,
m), 8.33 (1H, dd, J=1.0, 7.3 Hz), 8.56 (1H, d, J=6.4 Hz), 8.58 (1H,
d, J=6.4 Hz), 8.83 (1H, d, J=5.9 Hz), 9.27 (1H, d, J=1.0 Hz), 9.41
(1H, d, J=1.0 Hz).
EXAMPLE 54
The amorphous compound obtained in Example 53 was subjected to
alkaline hydrolysis according to the procedure described in Example
36 to obtain
N-{1-(p-hydroxybenzyl)-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5
-isoquinolinesulfonamide as yellow crystals,
Melting point: 157.degree.-160.degree. C. (decomposed);
IR (KBr) cm.sup.-1 : 1615, 1510, 1445, 1320, 1305, 1240 1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.46-2.74 (7H, m),
2.88-3.02 (5H, m), 3.00 (3H, s), 3.77 (3H, s), 4.06 (1H, m), 6.30
(2H, d, J=8.3 Hz), 6.65 (2H, d, J=8.3 Hz), 6.83 (2H, d, J=9.3 Hz),
6.88 (2H, d, J=9.3 Hz), 7.57 (1H, dd, J=7.3, 8.3 Hz), 8.12 (1H, d,
J=8.3 Hz), 8.13 (1H, d, J=6.4 Hz), 8.32 (1H, dd, J=1.0, 7.3 Hz),
8.50 (1H, d, J=6.4 Hz), 9.26 (1H, s).
EXAMPLE 55
The amorphous compound obtained in Example 52 was subjected to
alkaline hydrolysis according to the procedure described in Example
37, to obtain
N-{1-(p-hydroxybenzyl)-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-
5-isoquinolinesulfonamide as yellow crystals.
Melting point: 200.degree.-208.degree. C. (decomposed);
IR (KBr) cm.sup.-1 : 1615, 1590, 1510, 1450, 1340, 1230, 1150,
1130, 1025;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.20-2.44 (6H, m),
2.58-2.82 (6H, m), 3.33 (1H, m), 3.77 (3H, s), 5.55 (1H, br), 6.47
(2H, d, J=8.3 Hz), 6.76 (2H, d, J=8.3 Hz), 6.78 (2H, d, J=6.8 Hz),
6.83 (2H, d, J=6.8 Hz), 7.70 (1H, t, J=7.8 Hz), 8.21 (1H, d, J=8.3
Hz), 8.40 (1H, d, J=6.4 Hz), 8.44 (1H, dd, J=1.0, 7.3 Hz), 8.64
(1H, d, J=6.4 Hz), 9.34 (1H, s).
EXAMPLE 56
The same procedures as described in Reference Examples 12 to 14 and
Examples 34 and 35 were sequentially repeated except that
N-(2-methoxyphenyl)piperazine was used in place of
N-phenylpiperazine to obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-[4-(2-methoxyphenyl)piperazin
yl]ethyl}-N-methyl-5-isoquinolinesulfonamide, and 800 mg of the
compound was subjected to alkaline hydrolysis according to the
procedure described in Example 36 to obtain 504 mg of
N-{1-(p-hydroxybenzyl)-2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5
-isoquinolinesulfonamide in a light yellow amorphous form.
IR (KBr) cm.sup.-1 : 1610, 1590, 1500, 1320, 1230, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.5 (1H, dd, J=13.8, 10.0
Hz), 2.55-2.8 (2H, m), 2.9-3.0 (1H, m), 2.7 (4H, m), 3.0 (4H, m),
3.05 (3H, s), 3.86 (3H, s), 4.0 (1H, m), 6.23 (2H, d, J=8.3 Hz),
6.57 (2H, d, J=8.3 Hz), 6.8-7.1 (4H, m), 7.6 (1H, t, J=8.0 Hz),
8.14 (1H, d, J=6.1 Hz), 8.16 (1H, d, J=7.9 Hz), 8.35 (1H, dd,
J=7.4, 1.0 Hz), 9.30 (1H, s).
EXAMPLE 57
1-[2-Amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine in
crystals obtained in Reference Example 14 was reacted with
1-naphtharenesulfonyl chloride according to the procedure of
Example 34, and the product thus obtained was treated with methyl
iodide according to the procedure described in Example 35, to
obtain N-methyl-N-{1-[p-(.alpha.-naphtharenesulfonyloxy)
-benzyl]-2-(4-phenylpiperazinyl)ethyl}-.alpha.-naphtharenesulfonamide
in colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.26 (1H, dd, J=12.56, 6.85
Hz), 2.42 (4H,m), 2.48 (1H, dd, J=12.56, 6.85 Hz), 2.68 (1H, dd,
J=14.85, 6.85 Hz), 2.84 (1H, dd, J=14.85, 6.85 Hz), 2.85 (3H, s),
2.92 (4H,m), 4.12 (1H, quintet, J=6.85 Hz), 6.56 (2H, d, J=8.0 Hz),
6.78-6.92 (5H, m), 7.26 (2H, t, J=8.0 Hz), 7.42 (2H, t, J=8.0 Hz),
7.46-7.58 (2H, m), 7.68 (1H, dt, J=8.0, 1.0 Hz), 7.77-7.90 (2H, m),
7.90-8.07 (3H, m), 8.12 (1H, d, J=8.57 Hz), 8.17 (1H, dd, J=8.57,
1.0 Hz), 8.45 (1H, m), 8.84 (1H, d, J=9.14 Hz)
EXAMPLE 58
The amorphous compound obtained in Example 57 was subjected to
alkaline hydrolysis according to the procedure described in Example
36, to obtain
N-[1-(p-hydroxybenzyl)-2-(4-phenylpiperazinyl)ethyl]-N-methyl-.alpha.-naph
tharenesulfonamide in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1595, 1315, 1310, 1225, 1150, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.37 (1H, dd, J=13.70, 6.85
Hz), 2.47 (4H, m), 2.55 (1H, dd, J=13.70, 6.85 Hz), 2.72 (1H, dd,
J=14.28, 6.85 Hz), 2.85 (1H, dd, J=14.28, 6.85 Hz), 2.89 (3H, s),
2.97 (4H, m), 4.27 (1H, quinted, J=6.85 Hz), 5.10 (1H, br), 6.57
(2H, d, J=7.99 Hz), 6.78-6.89 (3H, m), 6.91 (2H, d, J=7.99 Hz),
7.25 (2H, t, J=7.99 Hz), 7.43 (1H, t, J=7.42 Hz), 7.50-7.63 (2H,
m), 7.86 (1H, dd, J=7.99, 1.0 Hz), 7.98 (1H, d, J=7.42 Hz), 8.22
(1H, dd, J= 7.42, 1.0 Hz), 8.56 (1H, dd, J=7.99, 1.0 Hz).
REFERENCE EXAMPLE 15
1-{[2-Amino-3-(P-Hydroxy)Phenyl]Propyl}-4-Benzyloxycarbonylpiperazine
1.41 g of
1-(N-tert-butoxycarbonyltyrosyl)-4-(benzyloxycarbonyl)piperazine
prepared according to the procedure described in Reference Example
11 was dissolved in 5.6 ml of absolute ethyl acetate, and to the
solution was added dropwise 11.25 ml of 4N hydrogen chloride in
ethyl acetate with stirring under ice cooling for two minutes, and
the reaction mixture was stirred for 2 hours at a room temperature.
After the reaction was completed, the solvent was evaporated off
under a reduced pressure, and to the residue was added 20 ml of 5%
sodium bicarbonate aqueous solution. The mixture was extracted with
30 ml and then 20 ml of a mixed solvent of chloroform/methanol
(9:1), and the extract was washed with saturated sodium chloride
aqueous solution, dried over magnesium sulfate and filtrated.
The filtrate was evaporated under a reduced pressure to obtain a
colorless foam. The foam was applied to a silica gel column and
eluted with chloroform/methanol (6:1), to obtain about 700 mg of
the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.2-2.8 (8H, m), 3.19 (1H,
m), 3.50 (7H, brs), 5.13 (2H, s), 6.71 (2H, d, J=8.5 Hz), 7.02 (2H,
d, J=8.5 Hz), 7.35 (5H, s).
EXAMPLE 59
N-{2-(4-Benzyloxycarbonylpiperazinyl)-1-[P-(5-Isoquinolinesulfonyloxy)Benzy
l]Ethyl}-5-Isoquinolinesulfonamide
680 mg of the amorphous compound obtained in Reference Example 15
was dissolved in 18 ml of absolute tetrahydrofuran, and to the
solution was added 1.27 g of 5-isoquinolinesulfonyl chloride.HCl,
and then was added dropwise 3.20 ml of triethylamine with stirring
under ice cooling for one minute, and the mixture was stirred at a
room temperature for 150 minutes. The reaction mixture was diluted
with 50 ml of chloroform, washed with water, and the washings was
extracted with 20 ml of chloroform. The combined organic extract
was washed with saturated sodium chloride aqueous solution, dried
over magnesium sulfate and filtered, and the filtrate was
evaporated under a reduced pressure. The resulting residue was
applied to a silica gel column, and eluted with chloroform/methanol
(100:1) to obtain 987 mg of the title compound in a light yellow
amorphous form.
IR (KBr) cm.sup.-1 : 1700, 1620, 1500, 1370, 1230, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8-2.2 (6H, m), 2.7-3.4
(7H, m), 5.05 (2H, s), 5.36 (1H, brs), 6,67 (2H, d, J=8.4 Hz), 6.89
(2H, d, J=8.4 Hz), 7.2-7.4 (5H, m), 7.62 (1H, d, J=7.7 Hz), 7.69
(1H, d, J=7.7 Hz), 8.2-8.5 (5H, brs), 8.52 (1H, d, J=6.2 Hz), 8.68
(1H, d, J=6.2 Hz), 8.81 (1H, d, J=5.9 Hz), 9.34 (1H, s), 9.41 (1H,
s).
EXAMPLE 60
N-{2-(4-Benzyloxycarbonylpiperazinyl)-1-[P-(5-Isoquinolinesulfonyloxy)Benzy
l]Ethyl}-N-Methyl-5-Isoquinolinesulfonamide
852 mg of the amorphous compound obtained in Example 59 was
dissolved in 8.5 ml of absolute dimethylformamide, and to the
solution was added 59 mg of 60% sodium hydride with stirring under
ice cooling, and further was added 113 .mu.l of methyl iodide, and
the reaction mixture was stirred for 2 hours with ice cooling.
After the addition of 30 ml of ice water, the reaction mixture was
extracted with 30 ml, 20 ml and 20 ml of ethyl acetate, the
combined extract was washed with saturated sodium chloride aqueous
solution, dried over magnesium sulfate, filtered and concentrated
under a reduced pressure. The resulting residue was applied to a
silica gel column and eluted with chloroform/methanol (100:1) to
obtain 679 mg of the title compound in a light yellow amorphous
form.
IR (KBr) cm.sup.-1 : 1700, 1620, 1500, 1370, 1240, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.23 (5H, brs), 2.3-2.9
(3H, m), 2.83 (3H, s), 3.25 (4H, brs), 4.09 (1H, m), 5.11 (2H, s),
6.60 (2H, d, J=8.7 Hz), 6.86 (2H, d, J=8.7 Hz), 7.34 (5H, brs),
7.5-7.7 (2H, m), 8.12 (1H, d, J=8.2 Hz), 8.1-8.3 (4H, m), 8.56 (2H,
m), 8.84 (1H, d, J=6.1 Hz), 9.29 (1H, s), 9.41 (1H, s).
EXAMPLE 61
N-{2-[(4-Benzenesulfonyl)Piperazinyl]-1-[P-(5-Isoquinolinesulfonyloxy)Benzy
l]Ethyl}-N-Methyl-5-Isoquinolinesulfonamide
To 480 mg of the amorphous compound obtained in Example 60 was
added 3 ml of a solution of 30% hydrogen bromide in acetic acid,
and the mixture was stirred at a room temperature for 80 minutes.
Then 50 ml of ether was added to the mixture, which was then
stirred. The resulting precipitate was collected and washed with
ether and dried under a reduced pressure to obtain 567 mg of
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-piperazinyl-ethyl}-N-methyl-5
-isoquinolinesulfonamide.HBr as colorless crystals.
.sup.1 H-NMR (DMSO - d.sub.6 +D.sub.2 O, .delta. ppm): 3.06 (3H,
s), 3.46 (12H, brs), 4.24 (1H, brs), 6.08 (2H, d, J=8.5 Hz), 6.74
(2H, d, J=8.5 Hz), 7.93 (2H, m), 8.25 (1H, d, J=6.7 Hz), 8.35 (1H,
d, J=7.3 Hz), 8.5-8.8 (5H, m), 9.05 (1H, d, J=6.4 Hz), 9.86 (2H,
brs).
550 mg of the crystals thus obtained was suspended in 10 ml of
absolute tetrahydrofuran, and after stirring with ice cooling, to
the suspension were added 84 .mu.l of benzenesulfonyl chloride and
767 .mu.l of triethylamine, and the reaction mixture was stirred at
a room temperature for 140 minutes. Then 30 ml of chloroform and 20
ml of water were added to the reaction mixture, and after
separation of the layers, the aqueous layer was extracted with 20
ml of chloroform. The chloroform layers were combined, washed with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate, and filtered. The filtrate was evaporated under a reduced
pressure, and the resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (100:1) to obtain 331 mg
of the title compound in a light yellow amorphous form.
IR (KBr) cm.sup.-1 : 1620, 1500, 1440, 1330, 1170;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.1-2.5 (6H, m), 2.5-2.8
(6H, m), 2.78 (3H, s), 4.05 (1H, m), 6.60 (2H, d, J=8.7 Hz), 6.83
(2H, d, J=8.7 Hz), 7.37 (1H, t, J=7.8 Hz), 7.5-7.8 (6H, m), 7.98
(1H, d, J=7.9 Hz), 8.1-8.3 (4H, m), 8.49 (1H, d, J=6.1 Hz), 8.55
(1H, d, J=6.1 Hz), 8.84 (1H, d, J=6.1 Hz), 9.17 (1H, s), 9.42 (1H,
s)
EXAMPLE 62
N-{2-[(4-Benzenesulfonyl)Piperazinyl)-1-(P-Hydroxybenzyl)-Ethyl}-N-Methyl-5
-Isoquinolinesulfonamide
221 mg of the amorphous compound obtained in Example 61 was
dissolved in a mixed solution of 2.69 ml of methanol and 0.66 ml of
tetrahydrofuran, and to the solution was added 0.33 ml of 2N sodium
hydroxide aqueous solution. The reaction mixture was refluxed for
3.5 hours, and to the mixture were added 30 ml of chloroform and 20
ml of 10% ammonium chloride aqueous solution, and the resulting
layers were separated. The aqueous layer was extracted with 20 ml
of chloroform, and the chloroform layers were combined, washed with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate and filtered. The filtrate was evaporated under a reduced
pressure, and the resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (100:1) to obtain 146 mg
of the title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1620, 1510, 1440, 1320, 1160;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.3-2.5 (2H, m), 2.60 (4H,
brs), 2.6-2.8 (2H, m), 2.95 (3H, s), 3.01 (4H, brs), 3.92 (1H,
brs), 6.21 (2H, d, J=8.2 Hz), 6.51 (2H, d, J=8.2 Hz), 7.4-7.8 (6H,
m), 8.03 (1H, d, J=6.1 Hz), 8.09 (1H, d, J=8.2 Hz), 8.24 (1H, dd,
J=1.2, 7.3 Hz), 8.40 (1H, d, J=5.8 Hz), 8.68 (1H, brs), 9.23 (1H,
brs).
REFERENCE EXAMPLE 16
O-Benzyl-N-Benzyloxycarbonyltyrosinol
27.25 g of O-benzyl-N-benzyloxycarbonyltyrosine methyl ester was
dissolved in a mixed solvent of 185 ml of ethanol and 122 ml of
tetrahydrofuran, and to the solution were added 5.8 g of lithium
chloride and 5.2 g of sodium borohydride under ice cooling. The
reaction mixture was stirred at a room temperature for 18 hours,
and after the addition of 500 ml of saturated sodium chloride
aqueous solution, extracted twice with 300 ml of chloroform. The
extract was dried over magnesium sulfate and concentrated under a
reduced pressure to obtain 25.4 g of the title compound as
colorless crystals
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.79 (2H, d, J=7.4 Hz),
3.51-3.79 (2H, m), 3.89 (1H, m), 4.93 (1H, br), 5.04 (2H, s), 5.08
(2H, s), 6.90 (2H, d, J=8.6 Hz), 7.11 (2H, d, J=8.6 Hz), 7.26-7.46
(5H, m).
REFERENCE EXAMPLE 17
1-[2-Benzyloxycarbonylamino-3-(P-Benzyloxyphenyl)Propyl]-4-(Tert-Butoxycarb
onyl)Piperazine
5.6 g of the crystals obtained in Reference Example 16 was
dissolved in 70 ml of carbon tetrachloride, and after the addition
of 4.5 g of triphenylphosphine, the mixture was refluxed for 20
hours. The reaction mixture was filtered to remove insoluble
matter, and the filtrate was concentrated under a reduced pressure,
and the resulting residue was applied to a silica gel column and
eluted with hexane/ethyl acetate (6:1) to obtain 4.96 g of
2-benzyloxycarbonylamino-3-(p-benzyloxyphenyl)propyl chloride as
colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.76-2.90 (2H, m),
3.56-3.80 (2H, m), 4.39 (1H, m), 5.03 (2H, s), 5.05, 5.13 (Total
2H, each s), 6.85, 6.89 (Total 2H, each d, each J=8.3 Hz), 7.00,
7.09 (Total 2H, each d, each J=8.3 Hz), 7.23-7.45 (5H, m).
4.1 g of the above-crystals and 2.23 g of
N-(tert-butoxycarbonyl)piperazine were dissolved in 40 ml of
dimethylformamide, to the solution were added 1.8 g of methyl
iodide and 1.66 g of potassium carbonate, and the mixture was
stirred at 120.degree. C. for 3 hours. After the addition of 100 ml
of saturated sodium chloride aqueous solution, the reaction mixture
was extracted twice with 60 ml of chloroform, and the extract was
dried over magnesium sulfate and concentrated under a reduced
pressure. The resulting residue was applied to a silica gel column
and eluted with hexane/ethyl acetate (2:1) to obtain 2.69 g of the
title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.45 (9H, s), 2.22-2.49
(6H, m), 2.82 (2H, m), 3.36 (4H, m), 3.94 (1H, m), 4.83 (1H, br),
8.03 (2H, s), 5.09 (2H, s), 6.88 (2H, d, J=8.3 Hz), 7.06 (2H, d,
J=8.3 Hz), 7.30-7.45 (5H, m).
EXAMPLE 63
N-{2-[4-(Tert-Butoxycarbonyl)Piperazinyl]-1-[P-(5-Isoquinolinesulfonyloxy)B
enzyl]Ethyl}-5-Isoquinolinesulfonamide
1.6 g of the amorphous compound obtained in Reference Example 17
was dissolved in 25 ml of methanol, and to the solution was added
1.0 g of 5% palladium on carbon. The mixture was stirred in a
hydrogen atmosphere for 20 hours, and filtered to remove insoluble
matter. The filtrate was concentrated under a reduced pressure,
resulting residue was dissolved in 30 ml of tetrahydrofuran, and to
the solution were added 2.8 g of 5-isoquinolinesulfonyl
chloride.HCl and 4 ml of triethylamine under ice cooling. After
stirring at a room temperature for 3 hours, to the reaction mixture
was added 100 ml of water, and the mixture was extracted twice with
70 ml of chloroform, and the extract was dried over magnesium
sulfate and concentrated under a reduced pressure. The resulting
residue was applied to a silica gel column and eluted with
chloroform/methanol (100:1 to 50:1) to obtain 1.27 g of the title
compound in a yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.40 (9H, s), 1.75-2.18
(6H, m), 2.15-3.07 (6H, m), 3.27 (1H, m), 5.35 (1H, br), 6.67 (2H,
d, J=8.3 Hz), 6.90 (2H, d, J=8.3 Hz), 7.65 (1H, t, J=7.8 Hz), 7.69
(1H, t, J=7.8 Hz), 8.21 (1H, d, J=8.3 Hz), 8.27-8.32 (2H, m),
8.37-8.41 (2H, m), 8.53 (1H, d, J=6.4 Hz), 8.69 (1H, d, J=6.9 Hz),
8.82 (1H, d, J=6.4 Hz), 9.36 (1H, s), 9.43 (1H, s).
EXAMPLE 64
940 mg of the amorphous compound obtained in Example 63 was
dissolved in a mixed solvent of 7.5 ml of tetrahydrofuran and 7.5
ml of dimethylformamide, and to the solution were sequential added
67 mg of 60% sodium hydride and 0.11 ml of methyl iodide under ice
cooling, and the mixture was stirred at a room temperature for one
hour. After the addition of 30 ml of saturated sodium chloride
aqueous solution, the reaction mixture was extracted with 40 ml of
ethyl acetate, and the extract was washed with saturated sodium
chloride aqueous solution, dried over magnesium sulfate and
concentrated under a reduced pressure. Resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(60:1) to obtain 723 mg of
N-{2-[4-(tert-butoxycarbonyl)piperazinyl]-[p-(5-isoquinolinesulfonyloxy)be
nzyl]Ethyl}-N-methyl-5-isoquinolinesulfonamide in a yellow
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.44 (9H, s), 2.21 (5H, m),
2.40 (1H, dd, J=6.9, 12.6 Hz), 2.15 (1H, dd, J=7.4, 14.3 Hz), 2.83
(1H, dd, J=6.9, 14.3 Hz), 2.84 (3H, s), 3.17 (9H, m), 4.12 (1H, m),
6.60 (2H, d, J=8.8 Hz), 6.86 (2H, d, J=8.8 Hz), 7.58 (1H, t, J=7.8
Hz), 7.63 (1H, t, J=7.8 Hz), 8.13 (1H, d, J=8.3 Hz), 8.21-8.30 (4H,
m), 8.56 (1H, d, J=6.9 Hz), 8.57 (1H, d, J=5.9 Hz), 8.84 (1H, d,
J=5.9 Hz), 9.29 (1H, s), 9.42 (1 H, s).
EXAMPLE 65
To 720 mg of the amorphous compound obtained in Example 64 was
added 10 ml of 4N hydrochloric acid in ethyl acetate, and the
mixture was stirred at a room temperature for one hour and
concentrated under a reduced pressure. To the mixture was added 30
ml of saturated sodium bicarbonate aqueous solution, and the
reaction mixture was extracted twice with 20 ml of a mixed solvent
of chloroform/isopropanol (5:1). The extract was dried over
magnesium sulfate and concentrated to dryness under a reduced
pressure to obtain 620 mg of
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]ethyl-2-piperazinyl}-N-methyl-5-
isoquinolinesulfonamide in a yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.18-2.28 (5H, m), 2.37
(1H, dd, J=7.3, 12.7 Hz), 2.63 (4H, m), 2.66 (1H, dd, J=7.3, 14.8
Hz), 2.83 (3H, s), 2.86 (1H, dd, J=5.4, 14.8 Hz), 4.13 (1H, m),
6.61 (2H, d, J=8.8 Hz), 6.89 (2H, d, J=8.8 Hz), 7.59 (1H, t, J=7.8
Hz), 7.63 (1H, t, J=7.8 Hz), 8.12 (1H, d, J=8.3 Hz), 8.23-8.35 (4H,
m), 8.56 (1H, d, J=5.9 Hz), 8.58 (1H, d, J=6.4 Hz), 8.83 (1H, d,
J=6.9 Hz), 9.29 (1H, s), 9.42 (1H, s).
EXAMPLE 66
620 mg of the amorphous compound obtained in Example 65 was
dissolved in 10 ml of methylene chloride, to the solution were
added 0.29 ml of benzyl chloroformate and 0.4 ml of triethylamine
with ice cooling. The reaction mixture was stirred for two hours
with ice cooling, and after the addition of 40 ml of saturated
sodium chloride aqueous solution, extracted twice with 20 ml of
chloroform. The extract was dried over magnesium sulfate and
concentrated under a reduced pressure, and resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(60:1) to obtain 660 mg of light yellow amorphous product showing
the same .sup.1 H-NMR spectrum as that of the compound of Example
60.
EXAMPLE 67
650 mg of the amorphous compound obtained in Example 66 was
dissolved in 6 ml of methanol, and to the solution was added 2 ml
of 1N sodium hydroxide aqueous solution. The mixture was refluxed
for 2 hours, and after the addition of 30 ml of saturated sodium
chloride aqueous solution, extracted twice with 200 ml of a mixed
solvent of chloroform/isopropanol (5:1). The extract was dried over
magnesium sulfate and concentrated under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (80:1 to 50:1) to obtain 386 mg of
N-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-N-methyl-5
-isoquinolinesulfonamide in a yellow amorphous form
IR (KBr) cm.sup.-1 : 1693, 1510, 1425, 1320, 1235, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.39-2.55 (6H, m), 2.64
(1H, dd, J=6.4, 12.7 Hz), 2.87 (1H, dd, J=4.4, 4.6 Hz), 2.97 (3H,
s), 3.44 (4H, m), 4.03 (1H, m), 5.13 (2H, s), 6.28 (2H, d, J=8.3
Hz), 6.62 (2H, d, J=8.3 Hz), 7.36 (5H, s), 7.39 (1H, dd, J=7.3, 7.8
Hz), 8.09 (1H, d, J=5.9 Hz), 8.13 (1H, d, J=7.8 Hz), 8.26 (1H, d,
J=7.3 Hz), 8.48 (1H, d, J=5.9 Hz), 9.27 (1H, s).
EXAMPLE 68
In the amorphous compound obtained in Example 63, protecting group
of the piperazine moiety was removed according to the procedure
described in Example 65, and the deprotected intermediate was
treated according to the procedures described in Examples 66 and 67
to obtain
N-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-5-isoquino
linesulfonamide.
IR (KBr) cm.sup.-1 : 1670, 1510, 1425, 1320, 1230, 1150, 1125,
993;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.07-2.23 (4H, m), 2.30
(1H, dd, J=6.3, 13.2 Hz), 2.39 (1H, dd, J=7.8, 13.2 Hz), 2.62 (1H,
dd, J=6.8, 14.2 Hz), 2.76 (1H, dd, J=6.4, 14.2 Hz), 3.00-3.38 (5H,
m), 5.09 (2H, s), 6.41 (2H, d, J=8.3 Hz), 6.69 (2H, d, J=8.8 Hz),
7.33 (5H, s), 7.68 (1H, dd, J=7.3, 8.3 Hz) 8.21 (1H, d, J=8.3 Hz),
8.35 (1H, d, J=5.9 Hz), 8.40 (1H, dd, J=1.0, 7.3 Hz), 8.61 (1H, d,
J=5.9 Hz), 9.34 (1H, s).
EXAMPLE 69
The same procedure as described in Example 68 was repeated except
that phenylpropionyl chloride was used in place of benzyl
chloroformate, to obtain
N-{1-(p-hydroxybenzyl)-2-[4-(3-phenylpropyl)piperazinyl]ethyl}-5-isoquinol
inesulfonamide.
IR (KBr) cm.sup.-1 :1610, 1510, 1445, 1320, 1150, 1130, 993;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.00-2.20 (4H, m), 2.26
(1H, dd, J=5.9, 12.7 Hz), 2.36 (1H, dd, J=7.8, 12.7 Hz), 2.46-2.60
(2H, m), 2.62-2.77 (2H, m) 2.83-3.00 (2H, m), 3.00-3.41 (5H, m),
5.24 (1H, br), 6.43 (2H, d, J=8.3 Hz), 6.71 (2H, d, J=8.3 Hz),
7.13-7.34 (5H, m), 7.69 (1H, dd, J=7.3, 8.3 Hz), 8.20 (1H, d, J=7.8
Hz), 8.34 (1H, d, J=5.9 Hz), 8.40 (1H, dd, J=1.0, 7.3 Hz), 8.63
(1H, br), 9.12 (1H, br).
EXAMPLE 70
The same procedure as described in Example 68 was repeated except
that phenylisocyanate was used in place of benzyl chloroformate, to
obtain
N-[1-(p-hydroxybenzyl)-2-(4-phenylaminocarbonylpiperazinyl)ethyl]-5isoquin
olinesulfonamide in yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3 +CD.sub.3 OD, .delta. ppm): 2.37 (1H, dd,
J=8.8, 14.2 Hz), 2.65 (1H, dd, J=5.4, 13.7 Hz), 2.73-3.20 (4H, m),
3.40-3.95 (7H, m), 6.12 (2H, d, J=8.3 Hz), 6.50 (2H, d, J=8.3 Hz),
7.05 (1H, m), 7.25-7.38 (4H, m), 7.67 (1H, dd, J=7.8, 8.3 Hz), 8.21
(1H, d, J=7.8 Hz), 8.31 (1H, d, J=6.8 Hz), 8.53 (1H, br), 9.23 (1H,
br).
EXAMPLE 71
The same procedure as described in Example 68 was repeated except
that benzylisocyanate was used in place of benzyl chloroformate, to
obtain
N-[2-(4-benzylaminocarbonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-5-isoqui
nolinesulfonamide in a yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3 -CD.sub.3 OD, .delta. ppm): 2.40-2.71 (2H,
m), 2.76-3.23 (4H, m), 3.40-3.80 (7H, m), 4.39 (2H, s), 6.08 (2H,
d, J=8.3 Hz), 6.46 (2H, d, J=8.3 Hz), 7.20-7.38 (5H, m), 7.63 (1H,
t, J=7.8 Hz), 8.17 (1H, d, J=8.3 Hz), 8.29 (2H, d, J=6.9 Hz), 8.52
(1H, br), 9.23 (1H, br).
EXAMPLE 72
200 mg of the amorphous compound obtained in Example 67 was
dissolved in 5 ml of chloroform, and to the solution was added 1 ml
of methanol, and also a solution of diazomethane in ether with ice
cooling. The reaction mixture was stirred for 90 minutes and then
concentrated. Resulting residue was applied to silica gel column
and eluted with chloroform/methanol (80:1 to 50:1), to obtain 103
mg of
N-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-methoxybenzyl)ethyl]-N-methyl-5
-isoquinolinesulfonamide.
IR (KBr) cm.sup.-1 :1692, 1508, 1420, 1320, 1235, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.32-2.45 (5H, m),
2.53-2.65 (2H, m), 2.78-2.90 (1H, m) 2.92 (3H, s), 3.37 (4H, m),
3.73 (3H, s), 4.16 (1H, m), 5.11 (2H, s), 6.50 (2H, d, J=8.3 Hz)
6.82 (2H, d, J=8.3 Hz), 7.35 (5H, s), 7.55 (1H, t, J=7.8 Hz), 8.09
(1H, d, J=8.3 Hz), 8.18 (1H, d, J=6.4 Hz), 8.22 (1H, d, J=7.3 Hz),
8.55 (1H, d, J=6.4 Hz), 9.24 (1H, s).
EXAMPLE 73
The product of Example 68 was treated according to the procedure in
Example 72, to obtain
N-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-methoxybenzyl)ethyl]-5-isoquino
linesulfonamide.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.97-2.17 (4H, m), 2.19
(1H, dd, J=4.4, 13.7 Hz), 2.28 (1H, dd, J=6.8, 13.7 Hz), 2.70 (1H,
dd, J=6.8, 14.2 Hz), 2.82 (1H, dd, J=5.4, 14.2 Hz), 3.03 (2H, m),
3.15 (2H, m), 3.34 (1H, m), 3.74 (3H, s), 5.07 (2H, s), 5.36 (1H,
br), 6.59 (2H, d, J=8.8 Hz), 6.85 (2H, d, J=8.3 Hz), 7.27-7.37 (5H,
m), 7.68 (1H, dd, J=7.3, 7.8 Hz), 8.18 (1H, d, J=8.3 Hz), 8.39 (1H,
d, J=5.9 Hz), 8.42 (1H, dd, J=1.0, 7.8 Hz), 8.67 (1H, d, J=5.9 Hz),
9.33 (1H, s).
EXAMPLE 74
N-{2-(4-Benzoylpiperazinyl)-1-[P-(5-Isoquinolinesulfonyloxy)Benzyl]Ethyl}-N
-Methyl-5-Isoquinolinesulfonamide
764 mg of the intermediate crystals obtained in Example 61 was
suspended in 7 ml of tetrahydrofuran, to the suspension were added
135 mg of benzoyl chloride and 5 minutes later 1.1 ml of
triethylamine with ice cooling, and the mixture was stirred for one
hour. After adding chloroform and water, the reaction mixture was
extracted three times with 30 ml of chloroform, and the extract was
washed with saturated sodium chloride aqueous solution, dried over
magnesium sulfate and concentrated to dryness under a reduced
pressure. 0.82 g of the resulting pale yellow residue was applied
to a silica gel column and eluted with chloroform/methanol (100:1)
to obtain 198 mg of the title compound in a colorless amorphous
form.
IR (KBr) cm.sup.-1 :1620, 1370, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.2-2.8 (10H, m), 2.84 (3H,
s), 3.1-3.7 (4H, m), 4.14 (1H, m), 6.61 (2H, d, J=8.6 Hz), 6.85
(2H, d, J=8.6 Hz), 7.3-8.6 (14H, m), 8.84 (1H, d, J=5.8 Hz), 9.30
(1H, s) 9.43 (1H, s).
EXAMPLE 75
N-[2-(4-Benzoylpiperazinyl)-1-(P-Hydroxybenzyl)Ethyl]-N-Methyl-5-Isoquinoli
nesulfonamide
To 349 m of the amorphous compound obtained in Example 74 were
added 4 ml of methanol, 1 ml of tetrahydrofuran and 0.5 ml of 2N
sodium hydroxide, and after refluxing for 2 hours, to the reaction
mixture were added chloroform, water and sodium chloride. The
reaction mixture was three times extracted with 30 ml of
chloroform, and the extract was washed with saturated sodium
chloride aqueous solution, dried over magnesium sulfate and
concentrated under a reduced pressure to obtain 0.25 g of yellow
oil. The yellow oil was applied to a silica gel column and eluted
with chloroform/methanol (50:1) to obtain 145 mg of the title
compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 :1610, 1440, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.6-2.9 (8H, m), 2.99 (3H,
s), 3.2-3.9 (4H, m), 4.00 (1H, m), 6.25 (2H, d, J=8.5 Hz), 6.56
(2H, d, J=8.5 Hz), 7.41 (5H, s), 7.59 (1H, t, J=7.9 Hz), 8.08 (1H,
d, J=6.1 Hz), 8.15 (1H, d, J=7.9 Hz), 8.25 (1H, d, J=7.9 Hz), 8.46
(1H, d, J=6.1 Hz), 9.29 (1H, s)
EXAMPLE 76
The same procedures as described in Examples 74 and 75 were
sequentially repeated except that 470 mg of the intermediate
crystals in Example 61 and 113 mg of benzylsulfonyl chloride in
place of benzoyl chloride were used to obtain 116 mg of
N-[2-(4-benzylsulfonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-N-methyl-5-is
oquinolinesulfonamide in a colorless amorphous form.
IR (KBr) cm.sup.-1 :1610, 1320, 1150;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.3-2.9 (8H, m), 2.94 (3H,
s), 3.0-3.2 (4H, m), 4.03 (1H, m), 4.20 (2H, s), 6.26 (2H, d, J=8.2
Hz), 6.56 (2H, d, J=8.2 Hz), 7.40 (5H, s), 7.60 (1H, t, J=7.9 Hz),
8.07 (1H, d, J=6.4 Hz), 8.15 (1H, d, J=7.9 Hz), 8.22 (1H, d, J=7.9
Hz), 8.46 (1H, d, J=6.4 Hz), 9.29 (1H, s).
EXAMPLE 77
The same procedures as described in Examples 74 and 75 were
sequentially repeated except that 382 mg of the intermediate
crystals in Example 61 and 133 mg of 5-isoquinolinesulfonamide.HCl
in place of benzoyl chloride were used, to obtain
N-{1-(p-hydroxybenzyl]-2-[4-(5-isoquinolinesulfonyl)piperazinyl]ethyl}-N-m
ethyl-5-isoquinolinesulfonamide in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1610, 1320, 1150;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.3-2.8 (8H, m), 2.90 (3H,
s), 3.0-3.2 (4H, m), 3.95 (1H, m), 6.29 (2H, d, J=8.6 Hz), 6.53
(2H, d, J=8.6 Hz), 7.50 (1H, t, J=7.9 Hz), 7.75 (1H, t, J=7.9 Hz),
8.0-8.1 (2H, m), 8.17 (1H, d, J=7.9 Hz), 8.26 (1H, d, J=7.9 Hz),
8.3-8.5 (2H, m), 8.53 (1H, d, J=6.1 Hz), 8.70 (1H, d, J=6.1 Hz),
9.19 (1H, s), 9.39 (1H, s).
EXAMPLE 78
The same procedures as described in Examples 59 and 60 were
sequentially repeated except that .alpha.-naphtharenesulfonyl
chloride was used in place of 5-isoquinolinesulfonyl chloride.HCl,
to obtain
N-{2-(4-benzyloxycarbonylpiperazinyl)-1-[p-(.alpha.-naphtharenesulfonyloxy
)benzyl]ethyl}-N-methyl-.alpha.-naphtharenesulfonamide in a
colorless amorphous form.
IR (KBr) cm.sup.-1 :1700, 1365, 1130, 860, 765;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.05-2.25 (5H, m), 2.41
(1H, dd, J=13.13, 6.85 Hz), 2.55-2.8 (2H, m), 2.84 (3H, s),
3.05-3.25 (4H, m), 4.05 (1H, quintet, J=6.85 Hz), 5.11 (2H, s),
6.57 (2H, d, J=8.57 Hz), 6.82 (2H, d, J=8.57 Hz), 7.25-7.60 (9H,
m), 7.60-8.20 (8H, m), 8.42 (1H, m), 8.82 (1H, d, J=7.99 Hz).
EXAMPLE 79
The amorphous compound obtained in Example 78 was subjected to
alkaline hydrolysis according to the procedure in Example 62 to
obtain
N-[2-(4-benzyloxycarbonylpiperazinyl)-1-(p-hydroxybenzyl)ethyl]-N-methyl-.
alpha.-naphtharenesulfonamide in a colorless amorphous form.
IR (KBr) cm.sup.-1 :1695, 1670, 1310, 1240, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.15-2.4 (5H, m), 2.48 (1H,
dd, J=12.56, 7.42 Hz), 2.6-2.85 (2H, m), 2.87 (3H, s), 3.15-3.35
(4H, m), 4.20 (1H, quintet, J=6.85 Hz), 5.10 (2H, s), 5.13 (1H,
br), 6.58 (2H, d, J=7.99 Hz), 6.89 (2H, d, J=7.99 Hz), 7.33 (5H,
s), 7.44 (1H, t, J=7.42 Hz), 7.47-7.63 (2H, m), 7.8-7.93 (1H, m),
7.99 (1H, d, J=7.99 Hz), 8.15 (1H, dd, J=6.85, 1.0 Hz), 8.45-8.6
(1H, m).
EXAMPLE 80
N-{1-[P-(5-Isoquinolinesulfonyloxy)Benzyl-2-(4-Phenylhomopiperazinyl)Ethyl}
-5-Isoquinolinesulfonamide
The same procedure as described in Example 34 except that
1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylhomopiperazine was
used in place of
1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine, to obtain
the title compound in a yellow amorphous form.
IR (KBr) cm.sup.-1 :1620, 1600, 1365, 1135;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.10-2.36 (7H, m), 2.63
(1H, dd, J=6.8, 13.7 Hz), 2.76 (1H, dd, J=4.9, 13.7 Hz), 2.99-3.29
(6H, m), 6.53 (2H, d, J=8.3 Hz), 6.60 (2H, d, J=8.8 Hz), 6.64 (1H,
t, J=7.3 Hz), 6.80 (2H, d, J=8.8 Hz), 7.17 (1H, t, J=8.8 Hz), 7.62
(1H, t, J=7.8 Hz), 7.66 (1H, t, J=7.8 Hz), 8.18 (1H, d, J=8.3 Hz),
8.26 (2H, d, J=7.3 Hz), 8.37-8.38 (2H, m), 8.53 (1H, d, J=5.9 Hz),
8.67 (1H, d, J=6.4 Hz), 8.82 (1H, d, J= 5.9 Hz), 9.33 (1H, s), 9.42
(1H, s).
EXAMPLE 81
The amorphous compound obtained in Example 80 was treated with
methyl iodide according to the procedure in Example 35 to obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-(4-phenylhomopiperazinyl)ethy
l}-N-methyl-5-isoquinolinesulfonamide in a yellow amorphous
form.
IR (KBr) cm.sup.-1 :1620, 1600, 1500, 1365, 1135;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.70 (2H, m), 2.37 (1H, dd,
J=8.8, 11.7 Hz), 2.40-2.65 (6H, m), 2.76 (1H, dd, J=4.9, 13.7 Hz),
2.84 (3H, s), 3.23-3.42 (4H, m), 3.98 (1H, m), 6.51-6.65 (5H, m),
6.77 (2H, d, J=8.3 Hz), 7.16 (2H, t, J=7.8 Hz), 7.54 (1H, dd,
J=7.3, 8.3 Hz), 7.59 (1H, t, J=7.8 Hz), 8.08 (1H, d, J=7.8 Hz),
8.18-8.26 (4H, m), 8.55 (1H, d, J=5.9 Hz), 8.55 (1H, dd, J=1.0, 6.3
Hz), 8.84 (1H, d, J=6.3 Hz), 9.26 (1H, s), 9.41 (1H, d, J=1.0
Hz).
The amorphous compounds obtained in Examples 80 and 81 were
subjected to alkaline hydrolysis according to the procedure
described in Example 36, to obtain the following two compounds.
EXAMPLE 82
N-[1-(P-Hydroxybenzyl)-2-(4-Phenylhomopiperazinyl)Ethyl]-5-Isoquinolinesulf
onamide
Yellow crystals;
Melting point: 170.degree.-178.degree. C. (decomposed);
IR (KBr) cm.sup.-1 :1615, 1600, 1505, 1365, 1320, 1205, 1155,
1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.79 (2H, m), 2.44 (1H, dd,
J=8.3, 13.7 Hz), 2.50-2.72 (7H, m), 3.23 (1H, m), 3.30-3.45 (4H,
m), 6.24 (2H, d, J=8.3 Hz), 6.51 (2H, d, J=8.3 Hz), 6.66 (2H, d,
J=8.3 Hz), 6.68 (1H, t, J=7.3 Hz), 7.23 (2H, dd, J=7.3, 8.3 Hz),
7.64 (1H, t, J=7.8 Hz), 8.19 (1H, d, J=7.8 Hz), 8.27 (1H, d, J=6.4
Hz), 8.34 (1H, dd, J=1.0, 7.3 Hz), 8.53 (1H, d, J=6.4 Hz), 9.33
(1H, brs).
EXAMPLE 83
N-[1-(P-Hydroxybenzyl)-2-(4-Phenylhomopiperazinyl)Ethyl]-N-Methyl-5-Isoquin
olinesulfonamide
Yellow amorphous.
IR (KBr) cm.sup.-1 :1615, 1600, 1500, 1360, 1320, 1210, 1150,
1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.93 (2H, m), 2.40 (1H, dd,
J=9.8, 14.2 Hz), 2.56 (1H, dd, J=8.8, 12.7 Hz), 2.70 (2H, m),
2.80-2.92 (4H, m), 3.00 (3H, s), 3.46-3.53 (4H, m), 3.85 (1H, m),
6.19 (2H, d, J=8.3 Hz), 6.51 (2H, d, J=8.3 Hz), 6.65 (1H, t, J=7.3
Hz), 6.69 (2H, d, J=8.3 Hz), 7.21 (2H, dd, J=7.3, 8.8 Hz), 7.58
(2H, t, J=7.3 Hz), 8.07 (1H, d, J=6.4 Hz), 8.12 (1H, d, J=8.3 Hz),
8.27 (1H, dd, J=1.0, 7.3 Hz), 8.45 (1H, d, J=5.9 Hz), 9.27 (1H,
s)
REFERENCE EXAMPLE 18
N-Tert-Butoxycarbonyl-4-Hydroxypiperidine
7.14 g of 4-piperidone.monohydrate.hydrochloride was dissolved in
50 ml of dimethylformamide and 10 ml of water, and to the solution
were added 25 ml of diisopropylethylamine and 9.5 g of
di-tert-butyl dicarbonate at a room temperature with stirring, and
the reaction mixture was stirred for 4 hours. After adding water
and saturating with sodium chloride, the reaction mixture was
extracted twice with 300 ml of chloroform. The extract was dried
over magnesium sulfate and evaporated under a reduced pressure to
obtain 9.6 g of residue, which was then dissolved in 100 ml of
ethanol. To the solution was added 1.83 g of sodium borohydride
with stirring under ice cooling, and the mixture was stirred for 90
minutes under the same condition, and then for 30 minutes at a room
temperature. After adding saturated sodium chloride aqueous
solution, the reaction mixture was alkalized with sodium
bicarbonate and extracted twice with 600 ml of chloroform. The
extract was dried over magnesium sulfate and evaporated under a
reduced pressure, and resulting residue was subjected to a silica
gel column and eluted with hexane/ethyl acetate (2:1), to obtain
8.03 g of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.35-1.6 (2H, m), 1.45 (9H,
s), 1.75-1.95 (2H, m), 3.03 (2H, ddd, J=13.13, 10.28, 4.00 Hz),
3.75-3.95 (3H, m).
REFERENCE EXAMPLE 19
4-(P-Methylbenzyloxy)Piperidine
2.0 g of the amorphous compound obtained in Reference Example 18
was dissolved in 20 ml of dimethylformamide, to the solution was
added 0.48 g of 60% sodium hydride in an ice bath. After removing
from the ice bath, the reaction mixture was stirred at a room
temperature for 30 minutes, and after adding 1.54 g of
p-methylbenzyl chloride, further stirred for 18 hours. The reaction
mixture was poured on ice, saturated with sodium chloride and
extracted twice with 150 ml of chloroform. The extract was dried
over magnesium sulfate and evaporated under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with hexane/ethyl acetate (5:1) to obtain 1.27 g of
N-tert-butoxycarbonyl-4-p-methylbenzyloxypiperidine. This compound
was dissolved in 3 ml of ethyl acetate, and after adding 12 ml of
3N hydrogen chloride in ethyl acetate at a room temperature with
further stirring for 17 hours, the solvent was evaporated off under
a reduced pressure. Resulting residue was dissolved in water, and
the solution was alkalized with sodium bicarbonate, saturated with
sodium chloride and extracted twice with 200 ml of chloroform. The
extract was dried over magnesium sulfate and the solvent was
evaporated off under a reduced pressure to obtain 830 mg of the
title compound in colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.55-1.8 (2H, m), 1.9-2.15
(2H, m), 2.34 (3H, s), 2.81 (2H, ddd, J=13.13, 10.28, 4.00 Hz),
3.17 (2H, ddd, J=11.42, 7.42, 4.00 Hz), 3.56 (1H, septet, J=3.71
Hz), 4.50 (2H, s), 5.01 (1H, brs), 7.14 (2H, d, J=7.99 Hz), 7.22
(2H, d, J=7.99 Hz).
REFERENCE EXAMPLE 20
N-Tert-Butoxycarbonyl-O-(2-Methoxyethoxymethyl)Tyrosine Methyl
Ester
13.39 g of N-tert-butoxycarbonyltyrosine methyl ester was dissolved
in 65 ml of tetrahydrofuran and 65 ml of dimethylformamide, and to
the solution was added 1.9 g of 60% sodium hydride with stirring in
an ice bath. After removing from the ice bath, the mixture was
stirred at a room temperature for 30 minutes, and after addition of
5.4 g of methoxyethoxymethyl chloride with ice cooling, stirred for
15 hours allowing to warm to a room temperature. The reaction
mixture was poured on ice, saturated with sodium chloride and
extracted twice with 800 ml of chloroform. The extract was dried
over magnesium sulfate and the solvent was evaporated under a
reduced pressure, and resulting residue was applied to a silica gel
column and eluted with hexane/ethyl acetate (4:1) to obtain 13.85 g
of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.46 (9H, s), 3.02 (2H, m),
3.37 (3H, s), 3.5-3.6 (2H, m), 3.71 (3H, s), 3.75-3.85 (2H, m),
4.54 (1H, m), 4.95 (1H, m), 5.24 (2H, s), 6.96 (2H, d, J=9.71 Hz),
7.04 (2H, d, J=9.71 Hz).
REFERENCE EXAMPLE 21
2-(N-Tert-Butoxycarbonylamino)-1-Chloro-3-[P-(2-Methoxyethoxymethoxy)Phenyl
]Propane
13.85 g of the amorphous compound obtained in Reference Example 20
was dissolved in 90 ml of ethanol and 60 ml of tetrahydrofuran, and
to the solution were added 3.11 g of lithium chloride and 2.77 g of
sodium borohydride with stirring in an ice bath. After removing
from the ice bath, the mixture was stirred at a room temperature
for 16 hours, and after addition of satulated sodium chloride
aqueous solution, the reaction mixture was alkalized with sodium
bicarbonate and extracted twice with 800 ml of chloroform. The
extract was dried over magnesium sulfate and the solvent was
evaporated off under a reduced pressure, to obtain 11.73 g of
N-tert-butoxycarbonyl-o-(2-methoxyethoxymethyl)tyrosinol. This
compound was dissolved in 120 ml of of carbon tetrachloride, and to
the solution was added 10 g of triphenylphosphine. The mixture was
refluxed for 3 hours and further heated at 80.degree. C. for 17
hours. The solvent was evaporated off under a reduced pressure, and
the resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1) followed by with hexane/ethyl
acetate (4:1), to obtain 7.22 g of the title compound in colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.43 (9H, s), 2.75-2.9 (2H,
m), 3.38 (3H, s), 3.4-3.65 (4H, m), 3.75-3.9 (2H, m), 4.08 (1H, m),
4.79 (1H, m), 5.26 (2H, s), 6.99 (2H, d, J=9.71 Hz), 7.16 (2H, d,
J=9.71 Hz).
REFERENCE EXAMPLE 22
N-{2-(Tert-Butoxycarbonylamino)-3-[P-(2-Methoxyethoxymethoxy)Phenyl]Propyl}
-4-(P-Methylbenzyloxy)Piperidine
1.56 g of the amorphous compound obtained in Reference Example 21
was dissolved in 25 ml of dimethylformamide, to the solution were
added 0.83 g of the amorphous compound obtained in Reference
Example 19, 0.67 g of potassium carbonate and 0.67 g of sodium
iodide, and the mixture was stirred at 100.degree. C. for 2 hours,
and after adding saturated sodium chloride aqueous solution,
extracted twice with 150 ml of chloroform. The extract was dried
over magnesium sulfate and the solvent was evaporated off under a
reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (100:1) to obtain 490 mg
of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.42 (9H, s), 1.5-1.75 (3H,
m), 1.75-2.0 (2H, m), 2.0-2.3 (3H, m), 2.33 (3H, s), 2.55-2.95 (4H,
m), 3.25-3.5 (1H, m), 3.38 (3H, s), 3.5-3.65 (2H, m), 3.75-3.95
(3H, m), 4.49 (2H, s), 4.64 (1H, m), 5.25 (2H, s), 6.96 (2H, d,
J=9.71 Hz), 7.09 (2H, d, J=9.71 Hz), 7.14 (2H, d, J=9.71 Hz), 9.23
(2H, d, J=9.71 Hz).
EXAMPLE 84
N-{1-P-(5-Isoquinolinesulfonyloxy)Benzyl]-2-[4-P-Methylbenzyloxy)Piperidino
]ethyl}-5-Isoquinolinesulfonamide
490 mg of the amorphous compound obtained in Reference Example 22
was dissolved in 1 ml of ethyl acetate, and to the solution was
added 5 ml of 3N hydrogen chloride in ethyl acetate at a room
temperature with stirring, and the reaction mixture was stirred for
one-hour. After evaporating off the solvent, resulting residue was
alkalized with sodium bicarbonate aqueous solution, and the mixture
was saturated with sodium chloride, washed with a small amount of
methanol, and extracted twice with 100 ml of chloroform. The
extract was dried over magnesium sulfate, and the solvent was
evaporated off to obtain a residue comprising
N-[2-amino-3-(p-hydroxyphenyl)]propyl-4-(p-methylbenzyloxy)piperidine.
The residue was dissolved in 7 ml of tetrahydrofuran, and to the
solution were added 545 mg of 5-isoquinolinesulfonyl chloride.HCl
and 450 mg of triethylamine at a room temperature with stirring.
The reaction mixture was stirred for 18 hours, alkalized with a
sodium bicarbonate aqueous solution and extracted twice with 100 ml
of chloroform. The extract was dried over magnesium sulfate, and
the solvent was evaporated off under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (30:1) to obtain 572 mg of the title
compound in colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.0-1.33 (3H, m), 1.33-1.54
(1H, m), 1.59-1.88 (2H, m), 1.88-2.25 (4H, m), 2.33 (3H, s), 2.71
(1H, dd, J=14.28, 6.85 Hz), 2.91 (1H, dd, J=14.28, 4.57 Hz), 3.18
(2H, m), 4.34 (2H, s), 6.68 (2H, d, J=9.14 Hz), 6.90 (2H, d, J=9.14
Hz), 7.14 (4H, s), 8.13 (1H, t, J=7.42 Hz), 8.18 (1H, t, J=7.42
Hz), 9.19 (1H, d, J=7.42 Hz), 8.27 (2H, d, J=7.42 Hz), 8.40 (1H,
dd, J=7.99, 1.0 Hz), 8.44 (1H, d, J=6.85 Hz], 8.52 (1H, d, J=6.28
Hz), 8.68 (1H, d, J=6.28 Hz), 8.81 (1H, d, J=6.28 Hz), 9.34 (1H,
s), 9.41 (1H, s).
EXAMPLE 85
N-{1-(P-Hydroxybenzyl)-2-{4-(P-Methylbenzyloxy)Piperidino]Ethyl}-Isoquinoli
nesulfonamide
400 mg of the amorphous compound obtained in Example 84 was
dissolved in 2.5 ml of methanol and 2.5 ml of tetrahydrofuran, to
the solution was added 4 ml of 1N sodium hydroxide solution, and
the mixture was refluxed for 2 hours. After cooling, the reaction
mixture was diluted with water, acidified with citric acid and then
alkalized with sodium bicarbonate, and extracted twice with 100 ml
of chloroform. The extract was dried over magnesium sulfate, and
the solvent was evaporated off under a reduced pressure. Resulting
residue was applied to a silica gel column and eluted with
chloroform/methanol (20:1) to obtain 172 mg of the title compound
in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.2-1.75 (4H, m), 1.85-2.15
(2H, m), 2.2-2.58 (4H, m), 2.32 (3H, s), 2.58-2.85 (2H, m),
3.15-3.4 (2H, m), 4.41 (2H, s), 4.8 (2H, br), 6.42 (2H, d, J=9.14
Hz), 6.68 (2H, d, J=9.14 Hz), 7.14 (2H, d, J=7.42 Hz), 7.19 (2H, d,
J=7.42 Hz), 7.67 (1H, t, J=7.42 Hz), 8.19 (1H, d, J=7.42 Hz),
8.33-8.50 (2H, m), 8.58 (1H, d, J=6.28 Hz), 9.33 (1H, s).
EXAMPLE 86
The same procedure as described in Example 84 was repeated except
that
N-{2-(tert-butoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl
}-4-(3,4-dichlorobenzyloxy)piperidine was used in place of
N-{2-(tertbutoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl}
-4-(p-methylbenzyloxy]piperidine, to obtain
N-{1-[p-5-isoquinolinesulfonyloxy)benzyl]-2-[4-(3,4-dichlorobenzyloxy)
piperidino]ethyl}-5-isoquinolinesulfonamide in a colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 0.95-1.17 (1H, m),
1.17-1.34 (2H, m), 1.34-1.91 (2H, m), 1.91-2.30 (4H, m), 2.72 (1H,
dd, J=13.13, 7.42 Hz), 2.89 (1H, dd, J=13.13, 4.57 Hz), 3.20 (2H,
m), 4.33 (2H, s), 6.68 (2H, d, J=9.14 Hz), 6.92 (2H, d, J=9.14 Hz),
7.10 (1H, dd, J=9.14, 1.71 Hz), 7.36 (1H, d, J=1.71 Hz), 7.38 (1H,
d, J=9.14 Hz), 7.64 (1H, t, J=7.42 Hz), 7.68 (1H, t, J=7.42 Hz),
8.20 (1H, d, J=7.42 Hz), 8.28 (2H, d, J=7.42 Hz), 8.39 (1H, dd, J=
7.42, 1.0 Hz), 8.43 (1H, d, J=6.28 Hz), 8.53 (1H, d, J=6.28 Hz),
8.69 (1H, d, J=6.28 Hz), 8.80 (1H, d, J=6.28 Hz), 9.35 (1H, s),
9.42 (1H, s);
IR (KBr) cm.sup.-1 :1615, 1375, 1130, 860.
EXAMPLE 87
The amorphous compound obtained in Example 86 was subjected to
alkaline hydrolysis according to the procedure in Example 85, to
obtain
N-{1-(p-hydroxybenzyl)-2-[4-(3,4-dichlorobenzyloxy)piperidino]ethyl}-5-iso
quinolinesulfonamide in a colorless amorphous form.
IR (KBr) cm.sup.-1 :1615, 1375, 1130, 860;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.2-1.8 (4H, m), 1.9-2.2
(2H, m), 2.2-2.6 (4H, m), 2.62 (1H, dd, J=14.28, 6.85 Hz), 2.75
(1H, dd, J=14.28, 6.28 Hz), 3.29 (2H, m), 4.33 (2H, br), 4.39 (2H,
s), 6.38 (2H, d, J=8.57 Hz), 6.67 (2H, d, J=8.57 Hz), 7.12 (1H, dd,
J=8.57, 1.71 Hz), 7.38 (1H, d, J=8.57 Hz), 7.39 (1H, d, J=1.71 Hz),
7.67 (1H, t, J=7.42 Hz), 8.20 (1H, d, J=7.42 Hz), 8.37 (1H, d,
J=6.28 Hz), 8.40 (1H, dd, J=7.42, 1.0 Hz), 8.58 (1H, d, J= 6.28
Hz), 9.32 (1H, s).
REFERENCE EXAMPLE 23
The same procedure as described in Reference Example 21 was
repeated, except that N-benzyloxycarbonyl-o-benzyltyrosine methyl
ester was used in place of
N-tert-butoxycarbonyl-o-(2-methoxyethoxymethyl)tyrosine methyl
ester, to obtain
2-benzyloxycarbonylamino-3-(p-benzyloxyphenyl)-1-chloropropane in
colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.7-2.95 (2H, m), 3.49 (1H,
dd, J=11.42, 3.43 Hz), 3.63 (1H, dd, J=11.42, 4.00 Hz), 4.13 (1H,
m), 5.00 (1H, m), 5.04 (2H, s), 5.10 (2H, s), 6.92 (2H, d, J=7.99
Hz), 7.15 (2H, d, J=7.99 Hz), 7.3-7.5 (5H, m).
To the amorphous compound so obtained was added N-phenylpiperazine,
and the same procedure as described in Reference Example 21 was
repeated to obtain
1-{2-(benzyloxycarbonylamino)-3-(p-Benzyloxyphenyl)propyl}-4-phenylpiperaz
ine in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.34 (2H, d, J=6.85 Hz),
2.4-2.7 (4H, m), 2.75-3.0 (2H, m), 3.14 (4H, t, J=5.14 Hz), 3.99
(1H, m), 4.90 (1H, m), 5.04 (2H, s), 5.10 (2H, s), 6.75-7.0 (5H,
m), 7.09 (2H, d, J=8.57 Hz), 7.2=7.5 (12H, m)
EXAMPLE 88
N-{1-[(P-Benzyloxy)Benzyl-2-(4-Phenylpiperazinyl)Ethyl}-5-Isoquinolinesulfo
namide
500 mg of the 1-substituted 4-phenylpiperazine obtained in
Reference Example 23 was dissolved in 1 ml of acetic acid, and to
the solution was added 2 ml of 30% hydrogen bromide in acetic acid,
and the mixture was stirred for 10 minutes and poured on ice. After
adding saturated sodium thiosulfate aqueous solution, the reaction
mixture was alkalized with saturated sodium bicarbonate aqueous
solution, and extracted twice with 150 ml of chloroform. The
extract was dried over magnesium sulfate and the solvent was
evaporated off under a reduced pressure, and resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(30:1), to obtain 235 mg of
1-{2-amino-3-(p-benzyloxyphenyl)propyl}-4-phenylpiperazine. 235 mg
of this compound was dissolved in 5 ml of tetrahydrofuran, and to
the solution were added 195 mg of 5-isoquinolinesulfonyl
chloride.HCl and 178 mg of triethylamine at a room temperature with
stirring, and the mixture was stirred for 16 hours. After adding
saturated sodium chloride aqueous solution, the reaction mixture
was alkalized with sodium bicarbonate aqueous solution, and
extracted twice with 150 ml of chloroform. The extract was dried
over magnesium sulfate, and the solvent was evaporated off under a
reduced pressure, and resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (50:1) to obtain 280 mg
of
N-{1-[(4-benzyloxy)benzyl]-2-(4-phenylpiperazinyl)ethyl}-5-isoquinolinesul
fonamide in a calorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.1-2.5 (6H, m), 2.7-3.0
(6H, m), 3.37 (1H, m), 4.99 (2H, s), 5.5 (1H, br), 6.71 (2H, d,
J=8.57 Hz), 6.81 (3H, t, J=8.57 Hz), 6.90 (2H, d, J=8.57 Hz), 7.24
(2H, t, J=8.57 Hz), 7.3-7.5 (5H, m), 7.68 (1H, t, J=7.42 Hz), 8.17
(1H, d, J=7.99 Hz), 8.43 (1H, d, J=6.28 Hz), 8.46 (1H, d, J=6.85
Hz), 8.67 (1H, d, J=6.28 Hz), 9.32 (1H, s).
EXAMPLE 89
N-{2-[4-(3,4-Dichlorobenzyloxy)Piperidino]-1-[P-(5-Isoquinolinesulfonyloxy)
Benzyl]Ethyl}-N-Methyl-5-Isoquinolinesulfonamide
1.70 g of the amorphous compound obtained in Example 86 was
dissolved in 10 ml of dimethylformamide, and to the solution was
added 93 mg of sodium hydride with stirring in an ice bath, and
after stirring for 10 minutes the ice bath was removed. The
reaction mixture was stirred at a room temperature for 4 hours, and
after adding 150 ml of ethyl acetate, washed three times with water
and the washing were extracted with 50 ml of ethyl acetate. The
extracts were combined and washed with saturated sodium chloride
aqueous solution, dried over magnesium sulfate, and the solvent was
evaporated off under a reduced pressure. Resulting residue was
applied to a silica gel column (silica gel: Fuji Debison Kagaku,
BW-820MH), and eluted with 1% methanol in chloroform to obtain 1.30
g of the title compound in a colorless amorphous form.
IR (CHCl.sub.3) cm.sup.-1 :2920, 2810, 1618, 1583, 1563, 1450, 983,
902;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.30-1.52 (2H, m),
1.60-1.78 (2H, m), 1.95-2.12 (2H, m), 2.15-3.00 (6H, m), 2.84 (3H,
s), 3.31 (1H, m), 4.10 (1H, m), 4.42 (2H, s), 6.58 (2H, brd, J=8.5
Hz), 6.87 (2H, brd, J=8.5 Hz), 7.14 (1H, dd, J=8.3, 1.9 Hz), 7.39
(1H, d, J=8.3 Hz), 7.41 (1H, d, J=1.9 Hz), 7.53-7.65 (2H, m), 8.11
(1H, d, J=8.3 Hz), 8.28-8.31 (3H, m), 8.32 (1H, dd, J=7.5, 1.2 Hz),
8.54 (1H, brd, J=6.1 Hz), 8.57 (1H, d, J=6.1 Hz), 8.83 (1H, d,
J=6.1 Hz), 9.28 (1H, d, J=1.0 Hz), 9.41 (1H, d, J=1.0 Hz).
EXAMPLE 90
N-{2-[4-(3,4-Dichlorobenzyloxy)Piperidino]-1-(P-Hydroxybenzyl)Ethyl}-N-Meth
yl-5-Isoquinolinesulfonamide
1.04 g of the amorphous compound obtained in Example 89 was
dissolved in 10 ml of dimethylsulfoxide, to the solution was added
a solution of 152 mg of sodium hydroxide in 2 ml of water, and the
mixture was stirred at 80.degree. C. for 2 hours. After adding 150
ml of ethyl acetate, the reaction mixture was twice washed with 100
ml of water, and the washings were extracted with 50 ml of ethyl
acetate. The ethyl acetate layers were combined, washed with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate and evaporated to remove the solvent under a reduced
pressure. Resulting residue was applied to a silica gel column and
eluted with 1% methanol in chloroform to obtain 650 mg of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.50-1.67 (2H, m),
1.75-1.94 (2H, m), 2.15-2.30 (2H, m), 2.40-2.96 (6H, m), 3.00 (3H,
s), 3.39 (1H, m), 3.96 (1H, m), 4.47 (2H, s), 6.26 (2H, brd, J=8.5
Hz), 6.61 (2H, brd, J=8.5 Hz), 6.90-7.10 (1H, br), 7.16 (1H, dd,
J=8.3, 1.9 Hz), 7.41 (1H, d, J=8.3 Hz), 7.44 (1H, d, J=1.9 Hz),
7.60 (1H, dd, J=8.0, 7.5 Hz), 8.09 (1H, brd, J=6.1 Hz), 8.14 (1H,
brd, J=8.0 Hz), 8.31 (1H, dd, J=7.5, 1.2 Hz), 8.47 (1H, d, J=6.1
Hz), 9.28 (1H, brs).
EXAMPLE 91
N-{2-[4-(3,4-Dichlorobenzyloxy)Piperidine]-1-(P-Methoxybenzyl)Ethyl}-N-Meth
yl-5-Isoquinolinesulfonamide
350 mg of the amorphous compound obtained in Example 90 was
dissolved in 10 ml of dimethylformamide, and to the solution 82.8
mg of methyl iodide was added with stirring in an ice bath. The
mixture was stirred for 30 minutes, and after removing the ice bath
further stirred for 2 hours at a room temperature. To the reaction
mixture was added 100 ml of ethyl acetate, and the mixture was
washed three times with 50 ml of water. The washing were extracted
with 50 ml of ethyl acetate, the ethyl acetate layer was washed
with water. The ethyl acetate layers were combined, washed with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate, and evaporated to remove the solvent under a reduced
pressure. Resulting residue was applied to a silica gel column and
eluted with 1% methanol in chloroform to obtain 297 mg of the title
compound in a colorless amorphous form.
IR (CHCl.sub.3)cm.sup.-1 : 2910, 2835, 1615, 1585, 1322, 1125,
986;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.38-1.60 (2H, m),
1.69-1.85 (2H, m), 2.06-2.22 (2H, m), 2.36 (1H, dd, J=13.0, 7.3
Hz), 2.51-2.76 (4H, m), 2.88 (1H, m), 2.93 (3H, s), 3.34 (1H, m),
3.73 (3H, s), 4.13 (1H, m), 4.44 (2H, s), 6.50 (2H, dm, J=8.8 Hz),
6.83 (2H, dm, J=8.8 Hz), 7.14 (1H, dd, J=8.0, 1.9 Hz), 7.40 (1H, d,
J=8.0 Hz), 7.43 (1H, d, J=1.9 Hz), 7.56 (1H, dd, J=8.3, 7.3 Hz),
8.08 (1H, brd, J=8.3 Hz), 8.29 (1H, dd, J=7.3, 1.2 Hz), 8.55 (1H,
d, J=6.3 Hz), 9.23 (1H, brs)
EXAMPLE 92
The same procedures as described in Examples 34 and 35 were
sequentially repeated except that
1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperidine was used
in place of
1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine, to obtain
N-{1-[p-(5-isoquinolinesulfonyloxy)benzyl]-2-(4-phenylpiperidino)ethyl}-N-
methyl-5-isoquinolinesulfonamide in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.15-1.75 (4H, m),
1.80-2.10 (2H, m), 2.20-2.50 (3H, m), 2.60-2.80 (2H, m), 2.80-3.05
(3H, m), 2.86 (3H, s), 4.13 (1H, d, J=6.85 Hz), 6.62 (2H, d, J=7.99
Hz), 6.91 (2H, d, J=7.99 Hz), 7.12 (2H, dd, J=6.85, 1.0 Hz),
7.16-7.40 (3H, m), 7.58 (1H, t, J=7.42 Hz), 7.61 (1H, t, J=7.42
Hz), 8.11 (1H, d, J=7.42 Hz), 8.26 (3H, dd, J=6.85, 1.0 Hz), 8.36
(1H, dd, J=7.42, 1.0 Hz), 8.56 (1H, d, J=6.28 Hz), 8.59 (1H, d,
J=6.28 Hz), 8.83 (1H, d, J=6.28 Hz), 9.28 (1H, s), 9.41 (1H, d,
J=1.0 Hz).
EXAMPLE 93
The amorphous compound obtained in Example 92 was subjected to
alkaline hydrolysis according to the procedure in Example 36, to
obtain
N-[1-(p-hydroxybenzyl)-2-(4-phenylpiperidino)ethyl]-N-methyl-5-isoquinolin
esulfonamide in a colorless amorphous form.
IR (KBr) cm.sup.-1 :1615, 1515, 1325, 1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.55-1.95 (5H, m), 2.22
(2H, dt, J=6.28, 1.7 Hz), 2.35-2.60 (3H, m), 2.70 (1H, dd, J=12.56,
5.71 Hz), 2.8-3.25 (3H, m), 3.06 (3H, s), 3.98 (1H, m), 6.23 (2H,
d, J=8.57 Hz), 6.59 (2H, d, J=8.57 Hz), 7.15-7.40 (5H, m), 7.62
(1H, t, J=7.42 Hz), 8.10 (1H, d, J=6.85 Hz), 8.16 (1H, d, J=7.42
Hz), 8.35 (1H, dd, J=7.42, 1.0 Hz), 8.47 (1H, d, J=6.28 Hz), 8.29
(1H, s)
EXAMPLE 94
The same procedures as described in Examples 34 and 35 were
sequentially repeated except that
1-[2-amino-3-(p-hydroxyphenyl)propyl]-4,4-ethylenedioxypiperidine
was used in place of
1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-phenylpiperazine, to obtain
N-{2-(4,4-ethylenedioxypiperidino)-1-[p-(5-isoquinolinesulfonyloxy)benzyl]
ethyl}-N-methyl-5-isoquinolinesulfonamide in a colorless amorphous
form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.4-1.6 (4H, m), 2.22 (1H,
dd, J=12.56, 6.85 Hz), 2.25-2.5 (5H, m), 2.6-2.8 (1H, m), 2.8-2.95
(1H, m), 2.84 (3H, s), 3.90 (4H, s), 4.11 (1H, q, J=6.85 Hz), 6.61
(2H, d, J=8.57 Hz), 6.89 (2H, d, J=8.57 Hz), 7.61 (1H, t, J=7.42
Hz), 7.63 (1H, t, J=7.42 Hz), 8.12 (1H, d, J=7.42 Hz), 8.26 (2H, d,
J=7.42 Hz), 8.27 (1H, d, J=7.42 Hz), 8.35 (1H, d, J=7.42 Hz), 8.57
(1H, d, J=6.28 Hz), 8.58 (1H, d, J=6.28 Hz), 8.84 (1H, d, J=6.28
Hz), 9.29 (1H, s), 9.42 (1H, s).
EXAMPLE 95
N-{1-[P-(5-Isoquinolinesulfonyloxy)Benzyl]-2-(4-Oxopiperidino)Ethyl}-N-Meth
yl-5-Isoquinolinesulfonamide
2.57 g of the product of Example 94 was dissolved in 50 ml of 3N
hydrochloric acid, and after refluxing for 6 hours and then
cooling, the reaction mixture was alkalized with saturated sodium
bicarbonate aqueous solution and extracted twice with 200 ml of
chloroform. The extract was dried over magnesium sulfate and
evaporated under a reduced pressure to remove the solvent, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (50:1) to obtain 2.22 g of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.1-2.25 (4H, m), 2.31 (1H,
dd, J=13.13, 6.85 Hz), 2.4=2.65 (6H, m), 2.65-2.85 (1H, m), 2.79
(3H, s), 4.10 (1H, q, J=6.85 Hz), 6.52 (2H, d, J=7.71 Hz), 6.78
(2H, d, J=7.71 Hz), 7.49 (1H, t, J=7.42 Hz), 7.55 (1H, t, J=7.42
Hz), 8.05 (1H, d, J=7.99 Hz), 8.10-8.20 (3H, m), 8.20 (1H, d,
J=7.42 Hz), 8.46 (1H, d, J=6.28 Hz), 8.48 (1H, d, J=6.28 Hz), 8.76
(1H, d, J=6.28 Hz), 9.20 (1H, s), 9.34 (1H, s).
EXAMPLE 96
N-{2-[4-(N'-Benzyl-N'-Methylamino)Piperidino]-1-[P-(5-Isoquinolinesulfonylo
xy)Benzyl]Ethyl}-N-Methyl-5-Isoquinolinesulfonamide
1.0 g of the product of Example 95 was dissolved in 15 ml of
methanol, to the solution were added 270 mg of benzylmethylamine
and 120 mg of sodium cyanoborohydride at a room temperature with
stirring, and the reaction mixture was stirred for 18 hours. After
addition of saturated sodium bicarbonate aqueous solution, the
reaction mixture was twice extracted with 150 ml of chloroform. The
extract was dried over magnesium sulfate and evaporated under a
reduced pressure to remove the solvent, and resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(30:1), to obtain 380 mg of the title compound in a colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.0-1.45 (2H, m), 1.45-1.65
(1H, m), 1.65-2.0 (3H, m), 2.13 (3H, s), 2.15-2.45 (3H, m), 2.5-2.9
(4H, m), 2.84 (3H, s), 3.49 (3H, s), 4.07 (1H, q, J=6.85 Hz), 6.61
(2H, d, J=7.99 Hz), 6.89 (2H, d, J=7.99 Hz), 7.28 (5H, s), 7.58
(1H, t, J=7.42 Hz), 7.60 (1H, t, J=7.42 Hz), 8.11 (1H, d, J=7.99
Hz), 8.25 (1H, d, J=6.28 Hz), 8.26 (2H, d, J=7.42 Hz), 8.34 (1H,
dd, J=7.42, 1.0 Hz), 8.55 (1H, d, J=6.28 Hz), 8.57 (1H, d, J=6.28
Hz), 8.83 (1H, d, J=6.28 Hz), 9.26 (1H, s), 9.41 (1H, s).
EXAMPLE 97
N-{2-[4-(N-Benzyl-N-Methylamino)Piperidino]-1-(P-Hydroxybenzyl)Ethyl}-N-Met
hyl-5-Isoquinolinesulfonamide
380 mg of the amorphous compound obtained in Example 96 was
dissolved in 2 ml of tetrahydrofuran and ml of methanol, to the
solution was added 4 ml of 1N sodium hydroxide aqueous solution,
and the mixture was refluxed for 3 hours and cooled. The reaction
mixture was poured to water, acidified with citric acid and then
alkalized with sodium bicarbonate, washed with a small amount of
methanol, and extracted twice with 100 ml of chloroform. The
extract was dried over magnesium sulfate and evaporated to remove
the solvent under a reduced pressure, and resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(20:1) to obtain 147 mg of the title compound in a colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.35-1 95 (4H, m),
1.95-2.25 (2H, m), 2.19 (3H, s), 2.3-2.7 (4H, m), 2.75-3.15 (3H,
m), 3.01 (3H, s), 3.57 (2H, s), 3.95 (1H, m), 6.25 (2H, d, J=8.3
Hz), 6.58 (2H, d, J=8.55 Hz), 7.2-7.4 (5H, m), 7.60 (1H, t, J=7.57
Hz), 8.11 (1H, d, J=5.86 Hz), 8.12 (1H, d, J=8.06 Hz), 8.32 (1H, d,
J=7.33 Hz), 8.46 (1H, d, J=6.35 Hz), 9.28 (1H, s).
EXAMPLE 98
The same procedures as described in Examples 96 and 97 were
sequentially repeated except that benzylamine was used in place of
benzylmethylamine, to obtain
N-{2-[4-(N-benzylamino)piperidino]-1-(p-hydroxybenzyl)ethyl}-N-methyl-5-is
oquinolinesulfonamide in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.2-1.6 (2H, m), 1.7-2.0
(2H, m), 2.0-2.3 (2H, m), 2.35-2.7 (4H, m), 2.7-3.5 (3H, m), 3.0
(3H, s), 3.83 (2H, s), 3.95 (1H, m), 6.24 (2H, d, J=7.99 Hz), 6.56
(2H, d, J=7.99 Hz), 7.32 (5H, m), 7.59 (1H, t, J=7.42 Hz), 8.10
(1H, d, J=6.28 Hz), 8.12 (1H, d, J=7.42 Hz), 8.30 (1H, d, J=7.42
Hz), 8.46 (1H, d, J=6.28 Hz), 9.26 (1H, s).
EXAMPLE 99
N-{2-(4-Hydroxypiperidino)-1-[P-(5-Isoquinolinesulfonyloxy)Benzyl]Ethyl}-N-
Methyl-5-Isoquinolinesulfonamide
200 mg of the amorphous compound obtained in Example 95 was
dissolved in 5 ml of methanol, to the solution was added in
portions 35.2 mg of sodium borohydride at a room temperature with
stirring, and the mixture was stirred for 2 hours and evaporated to
remove the solvent. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (100:4), to obtain 116
mg of the title compound as pale yellow oil.
IR (KBr) cm.sup.-1 :1620, 1500, 1370, 1320, 1130, 860;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.2-1.4 (2H, m), 1.5-1.8
(4H, m), 1.9-2.1 (2H, m), 2.25 (1H, dd, J=12.6, 7.3 Hz), 2.4 (1H,
dd, J=12.7, 7.1 Hz), 2.7 (1H, dd, J=13.8, 7.0 Hz), 2.8-2.95 (1H,
m), 2.55 (1H, brs), 2.83 (3H, s), 3.55 (1H, m), 4.1 (1H, m), 6.6
(2H, d, J=8.5 Hz), 6.87 (2H, d, J=8.5 Hz), 7.6 (1H, t, J=8.3 Hz),
7.63 (1H, t, J=7.8 Hz), 8.12 (1H, d, J=8.3 Hz), 8.23 (1H, d, J=5.1
Hz), 8.26 (1H, d, J=5.1 Hz), 8.3 (1H, dd, J=1.2, 3.3 Hz), 8.54 (1H,
d, J=4.1 Hz), 8.57 (1H, d, J=4.1 Hz), 8.83 (1H, d, J=6.1 Hz), 9.28
(1H, s), 9.4 (1H, s).
EXAMPLE 100
N-{2-(4-Hydroxypiperidino)-1-[P-(5-Isoquinolinesulfonyloxy)Benzyl]Ethyl}-N-
Methyl-5-Isoquinolinesulfonamide
150 mg of the oil obtained in Example 99 was dissolved in 3 ml of
methanol, to the solution was added 1 ml of 10% sodium hydroxide
aqueous solution, and the reaction mixture were refluxed for 2
hours and evaporated to remove the solvent under a reduced
pressure, the resulting residue was acidified with citric acid and
then alkali.+-.ed with a sodium bicarbonate aqueous solution, and
the mixture was extracted three times with 20 ml of chloroform. The
extract was dried over magnesium sulfate and evaporated to remove
the solvent under a reduced pressure, and the resulting residue was
subjected to a silica gel preparative thin layer chromatographic
and separated by chloroform/methanol (20:1), to obtain 87 mg of the
title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1610, 1510, 1320, 1150, 1125;
.sup.1 H-NMR (CDCl , .delta. ppm): 1.4-1.7 (2H, m), 1.8-2.0 (2H,
m), 2.1-2.4 (4H, m), 2.3-2.6 (1H, m), 2.7 (1H, dd, J=12.7, 4.8 Hz),
2.8 (1H, dd, J=14.6, 4.7 Hz), 2.95 (1H, dd, J=12, 2.5 Hz), 2.99
(3H, s), 3.7 (1H, m), 3.9 (1H, m), 6.15 (2H, d, J=8.3 Hz), 6.5 (2H,
d, J=8.3 Hz), 7.6 (1H, t, J=7.6 Hz), 8.0 (1H, d, J=6.1 Hz), 8.15
(1H, d, J=8.3 Hz), 8.33 (1H, dd, J=7.3, 1.0 Hz), 8.4 (1H, d, J=6.1
Hz), 9.24 (1H, s).
EXAMPLE 101
N-[
1-P-Hydroxybenzyl)-2-(4-Hydroxypiperidino)Ethyl]-N-Methyl-5-Isoquinolinesu
lfonamide
100 mg of the amorphous compound obtained by Example 100 was
dissolved in 5 ml of a mixture of ethyl acetate/methanol (1:1), to
the solution was added an excess amount of diazomethane in ether,
and the reaction mixture was allowed to stand overnight at a room
temperature. The solvent in the reaction mixture was evaporated off
under a reduced pressure, and resulting residue was subjected to a
silica gel preparative thin layer chromatography and separated by
chloroform/methanol (20:1) to obtain 80.4 mg of the title compound
in colorless amorphous form.
IR (KBr) cm.sup.-1 :1510, 1320, 1240, 1150, 1120, 1030;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.3-1.5 (2H, m), 1.7-2.0
(4H, m), 2.0-2.3 (2H, m), 2.35 (1H, dd, J=13.0, 7.1 Hz), 2.55 (1H,
dd, J=10.0, 6.9 Hz), 2.62 (1H, dd, J=10.3, 7.3 Hz), 2.89 (1H, dd,
J=14.8, 6.3 Hz), 2.6-2.75 (1H, m), 2.93 (3H, s), 3.6 (1H, m), 4.12
(1H, m), 3.73 (3H, s), 6.5 (2H, d, J=8.7 Hz), 6.84 (1H, d, J=8.7
Hz), 7.56 (1H, t, J=8.0 Hz), 8.1 (1H, d, J=8.3 Hz), 8.2 (1H, d,
J=6.1 Hz), 8.3 (1H, d, J=7.3 Hz), 8.55 (1 H, d, J=6.1 Hz), 9.24
(1H, s).
EXAMPLE 102
N-[1-(P-Acetoxybenzyl)-2-(4-Acetoxypiperidino)Ethyl]-N-Methyl-5-Isoquinolin
esulfonamide
230 mg of the amorphous compound obtained in Example 100 was
dissolved in 2 ml of pyridine, to the solution was added 1 ml of
acetic anhydride, and the reaction mixture was allowed to stand
overnight at a room temperature. To the mixture was added 20 ml of
ice water, and the mixture was stirred for one hour and extracted
twice with 20 ml of ethyl acetate. The extract was washed with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate and evaporated to remove the solvent under a reduced
pressure. Resulting residue was applied to a silica gel column and
eluted with chloroform/methanol (100:1) to obtain 234.3 mg of the
title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 :1760, 1730, 1360, 1320, 1240, 1215, 1200,
1030;
.sup.1 H-NMR (CDCl , .delta. ppm): 1.58 (3H, s), 2.03 (3H, s), 2.30
(3H, s), 2.91 (3H, s), 1.4-1.8 (4H, m), 2.2-2.9 (4H, m), 4.2 (1H,
m), 4.7 (1H, m), 6.77 (2H, d, J=6.6 Hz), 6.8 (2H, d, J=6.6 Hz), 7.5
(1H, t, J=8.0 Hz), 8.1 (1H, d, J=8.1 Hz), 8.2 (1H, d, J=7.4 Hz),
8.29 (1H, d, J=6.1 Hz), 8.57 (1H, d, J=6.1 Hz), 9.27 (1H, s).
EXAMPLE 103
The same procedure as described in Example 84 was repeated except
that
N-{2-(tert-butoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl
}-4-acetoxypiperidine synthesized in a similar manner was used in
place of
N-{2-(tert-butoxycarbonylamino)-3-[p-(2-methoxyethoxymethoxy)phenyl]propyl
}-4-(p-methylbenzyloxy)piperidine, to obtain
N-{2-[4-acetoxypiperidino]-1-[p-(5-isoquinolinesulfonyloxy)benyl]ethyl}-5-
isoquinolinesulfonamide in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 0.8-1.05 (1H, m), 1.2-1.55
(3H, m), 1.6-2.15 (5H, m), 1.99 (3H, s), 2.15-2.33 (1H, m), 2.73
(1H, dd, J=13.13, 6.85 Hz), 2.89 (1H, dd, J=13.13, 4.57 Hz), 3.22
(1H, m), 4.51 (1H, m), 5.43 (1H, br), 6.70 (2H, d, J=8.57 Hz), 6.91
(1H, d, J=8.57 Hz), 7.66 (1H, t, J=7.42 Hz), 7.68 (1H, d, J=7.42
Hz), 8.20 (1H, d, J=7.42 Hz), 8.30 (2H, d, J=7.42 Hz), 7.39 (1H,
dd, J=7.42, 1.0 Hz), 8.42 (1H, d, J=6.28 Hz), 8.53 (1H, d, J=6.29
Hz), 8.70 (1H, d, J=6.28 Hz), 8.81 (1H, d, J=6.28 Hz), 9.34 (1H,
s), 9.43 (1H, s).
EXAMPLE 104
N-{2-[4-Hydroxypiperidino]-1-[P-(5-Isoquinolinesulfonyloxy)Benzyl]Ethyl}-5-
Isoquinolinesulfonamide
1.5 g of the product obtained in the Example 103 was dissolved in 8
ml of methanol, to the solution was added 8 ml of 1N sodium
hydroxide aqueous solution, and the mixture was stirred for two
hours, and after adding water, extracted twice with 100 ml of
chloroform. The extract was washed with a saturated sodium chloride
aqueous solution, dried over magnesium sulfate and evaporated to
remove the solvent under a reduced pressure. The Resulting residue
was applied to a silica gel column an eluted with
chloroform/methanol (30:1), to obtain 800 mg of the title compound
in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 0.6-0.9 (1H, m), 1.05-1.3
(1H, m), 1.3-1.5 (2H, m), 1.5-1.9 (3H, m), 1.9-2.2 2.2 (2H, m),
2.2-2.4 (1H, m), 2.72 (1H, dd, J=13.70, 6.85 Hz), 2.89 (1H, dd,
J=1.82, 4.57 Hz), 3.19 (1H, m), 3.46 (1H, m), 6.72 (2H, d, J=8.57
Hz), 6.72 (2H, d, J=8.57 Hz), 7.66 (1H, t, J=7.42 Hz), 7.69 (1H, t,
J=7.42 Hz), 8.21 (1H, d, J=7.99 Hz), 8.29 (2H, d, J=7.42 Hz), 8.41
(1H, d, J=7.99 Hz), 8.44 (1H, d, J=6.28 Hz), 8.53 (1H, d, J=6.28
Hz), 8.69 (1H, d, J=6.28 Hz), 8.81 (1H, d, J=6.28 Hz), 9.35 (1H,
s), 9.42 (1 H, s).
EXAMPLE 105
N-3,4-Dichlorobenzyl-N-[1-(P-Hydroxybenzyl)-2-(4-Hydroxypiperidino)Ethyl]-5
-Isoquinolinesulfonamide
400 mg of the amorphous oompound obtained in Example 104 was
dissolved in 5 ml of dimethylformamide, to the solution were added
130 mg of 3,4-dichlorobenzyl chloride and 28 mg of 60% sodium
hydride with stirring under ice cooling, and the mixture was
allowed to warm to a room temperature and stirred for 18 hours.
After adding saturated sodium chloride aqueous solution, the
reaction mixture was extracted twice with 100 ml of chloroform, and
the extract was washed with saturated sodium chloride aqueous
solution, dried over magnesium sulfate and evaporated to remove the
solvent under a reduced pressure. The resulting residue was applied
to a silica gel column and eluted with chloroform/methanol (30:1),
to obtain 228 mg of
N-(3,4-dichlorobenzyl)-N-{2-(4-hydroxypiperidino)-1-[P-(5-isoquinolinesulf
onyloxy)benzyl]ethyl}-5-isoquinolinesulfonamide.
228 mg of the above compound was dissolved in 1.5 ml of methanol,
to the solution was added 1 ml of 1N sodium hydroxide aqueous
solution, and the mixture was refluxed for 3 hours and then cooled,
and after dilution with water, acidified with citric acid and then
alkalized with sodium bicarbonate, and extracted twice with 100 ml
of chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent, and resulting residue was applied
to a silica gel column and eluted with chloroform/methanol (20:1)
to obtain 162 mg of the title compound in a colorless amorphous
form.
.sup.1 H-NMR (CDCl , .delta. ppm): 1.2-1.6 (2H, m), 1.6-2.0 (3H,
m), 2.0-2.2 (2H, m), 2.4-2.9 (5H, m), 3.5 (1H, m), 4.21 (1H, q,
J=6.08 Hz), 4.44 (1H, d, J=16.36 Hz), 4.66 (1H, d, J=16.11 Hz),
6.51 (2H, d, J=8.55 Hz), 6.79 (2H, d, J=8.55 Hz), 7.17 (1H, dd,
J=8.30, 1.96 Hz), 7.25 (1H, d, J=8.06 Hz), 7.33 (1H, d, J=1.96 Hz),
7.57 (1H, t, J=7.57 Hz), 8.12 (1H, d, J=8.3 Hz), 8.25 (1H, d,
J=6.10 Hz), 8.33 (1H, dd, J=7.32, 0.98 Hz), 8.50 (1H, d, J=5.86
Hz), 9.21 (1H, s).
EXAMPLE 106
N-[1-(P-Hydroxybenzyl)-2-(4-Hydroxypiperidino)Ethyl]-N-P-Methylbenzyl-5-Iso
quinolinesufonamide
The same procedure as described in Example 105 was repeated except
that 4-methylbenzyl chloride was used in place of
3,4-dichlorobenzyl chloride was used to obtain the title compound
in colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3 +CD.sub.3 OD, .delta. ppm): 1.2-1.55 (2H,
m), 1.55-2.15 (5H, m), 2.33 (3H, s), 2.33-2.85 (5H, m), 3.5 (1H,
m), 3,98 (1H, q, J=6.59 Hz), 4.52 (1H, d, J=15.63 Hz), 4.78 (1H, d,
J=15.62 Hz), 6.36 (2H, d, J=8.05 Hz), 6.66 (2H, d, J=8.06 Hz), 7.08
(2H, d, J=7.56 Hz), 7.29 (2H, d, J=7.57 Hz), 7.60 (1H, t, J=7.57
Hz), 8.12 (1H, d, J=8.06 Hz), 8.28 (1H, d, J=6.10 Hz), 8.39 (1H, d,
J=7.32 Hz), 8.48 (1H, d, J=6.35 Hz), 9.20 (1 H, s).
EXAMPLE 107
N-{2-(4-Hydroxypiperidino)-1-[P-(5-Isoquinolinesulfonyloxy)Benzyl]Ethyl}-N-
Methyl-5-Isoquinolinesulfonamide
The amorphous compound obtained in Example 103 was treated with
methyl iodide according to the procedure in Example 89 and the
intermediate product was subjected to alkaline hydrolysis according
to the procedure in Example 104, to obtain the same product as in
Example 99.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.20-1.42 (2H, m), 1.68
(2H, m), 2.01 (2H, m), 2.22 (1H, dd, J=7.3, 13.2 Hz), 2.40 (1H, dd,
J=7.3, 13.2 Hz), 2.43-2.60 (2H, m), 2,66 (1H, dd, J=6.8, 13.7 Hz),
2.84 (3H, S), 2.85 (1H, dd, J=6.4, 13.7 Hz), 3,58 (1H, m), 4.10
(1H, m), 6.61 (2H, d, J=8.8 Hz), 6.88 (2H, d, J=8.8 Hz), 7.59 (1H,
t, J=7.8 Hz), 7.63 (1H, t, J=7.8 Hz), 8.12 (1H, d, J=8.3 Hz),
8.23-8.35 (4H, m), 8.55 (1H, d, J=6.4 Hz), 8.58 (1H, d, J=6.4 Hz),
8.83 (1H, d, J=5.9 Hz), 9.29 (1H, s), 9.42 {1H, s)
REFERENCE EXAMPLE 24
1-(N-Benzyloxycarbonyltyrosyl)-4-Phenylpiperazine
12.3 g of N-benzyloxycarbonyltyrosine and 6.6 g of
N-phenylpiperazine were dissolved in 150 ml of methylene chloride,
and to the solution was added 8.4 g of DCC, and the mixture was
stirred at a room temperature for 5 hours. Precipitated insoluble
matter was filtered off and the filtrate was concentrated under a
reduced pressure, and resulting residue was applied to a silica gel
column and eluted with hexane/ethyl acetate (1:1 to 1:2) to obtain
10.5 g of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.63 (1H, m), 2.88-3.24
(6H, m), 3.48 (1H, m), 3.68 (2H, m), 4.88 (1H, m), 5.07 (1H, d,
J=12.7 Hz), 5.11 (1H, d, J=12.7 Hz), 5.34 (1H, br), 5.67 (1H, d,
J=8.8 Hz), 6.71 (2H, d, J=8.3 Hz), 6.84 (2H, d, J=8.3 Hz), 6.90
(1H, t, J=7.3 Hz), 7.04 (2H, d, J=8.3 Hz), 7.26 (2H, t, J=7.3 Hz),
7.34 (5H, s).
EXAMPLE 108
1-[N,O-Bis(5-Isoquinolinesulfonyl)Tyrosyl]-4-Phenylpiperazine
4.59 g of the amorphous compound obtained in Reference Example 24
was dissolved in 50 ml of methanol, to the solution was added 3 g
of 5% palladium on carbon, and the mixture was stirred for 17 hours
at a room temperature in a hydrogen atmosphere. The resulting
insoluble matter was filtered off, and the filtrate was
concentrated under a reduced pressure to obtain a residue, which
was then suspended in 50 ml of chloroform. To the suspension were
sequentially added 5.7 g of 5-isoquinolinesulfonyl chloride.HCl and
10 ml of triethylamine with ice cooling, and then mixture was
stirred for 3 hours at a room temperature. After adding 200 ml of
water, the mixture was extracted twice with 100 ml of chloroform,
the extract was dried over magnesium sulfate and concentrated under
a reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (80:1 to 30:1), to
obtain 5.46 g of the title compound in a yellow amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.50-2.90 (7H, m),
2.92-3.17 (2H, m), 3.24 (1H, m), 4.32 (1H, m), 5.99 (1H, br), 6.65
(2H, d, J=8.8 Hz), 6.80 (2H, d, J=7.8 Hz), 6.89 (2H, d, J=8.8 Hz),
6.94 (1H, t, J=7.3 Hz), 7.29 (2H, dd, J=7.3, 8.3 Hz), 7.51 (1H, t,
J=7.8 Hz), 7.59 (1H, dd, J=7.3, 8.3 Hz), 8.09-8.31 (5H, m), 8.50
(1H, d, J=6.4 Hz), 8.69 (1H, d, J=5.9 Hz), 8.81 (1H, d, J=5.9 Hz),
9.28 (1H, s), 9.39 (1H, s).
EXAMPLE 109
1-[N,O-Bis(5-Isoquinolinesulfonyl)-N-Methyltyrosyl]-4-Phenylpiperazine
2.27 g of the amorphous compound obtained in Example 108 was
dissolved in 30 ml of dimethylformamide, to the solution were
sequentially added 160 mg of 60% sodium hydride and 0.3 ml of
methyl iodide with ice cooling, and the mixture was stirred for 90
minutes with ice cooling. After adding 80 ml of water, the reaction
mixture was extracted with 100 ml of ethyl acetate, and the extract
was washed with 80 ml of saturated sodium chloride aqueous
solution, dried over magnesium sulfate and concentrated under a
reduced pressure. The resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (60:1), to obtain 1.8 g
of the title compound in a yellow amorphous form.
IR (KBr) cm.sup.-1 :1668, 1475, 1360, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.45 (1H, dd, J=4.6, 13.1
Hz), 2.63 (1H, m), 2.82-3.07 (4H, m), 3.03 (3H, s), 3.13-3.29 (2H,
m), 3.43-3.65 (4H, m), 5.11 (1H, dd, J=4.6, 10.3 Hz), 6.76 (2H, d,
J=8.6 Hz), 6.85 (2H, d, J=8.0 Hz), 6.88 (1H, t, J=8.6 Hz), 7.29
(2H, dd, J=8.0, 8.6 Hz), 7.49 (1H, dd, J=8.3, 7.3 Hz), 7.70 (1H,
dd, J=8.3, 7.3 Hz), 8.16 (1H, dd, J=1.0, 7.3 Hz), 8.21 (2H, d,
J=8.3 Hz), 8.30 (1H, dd, J=1.0, 7.3 Hz), 8.41 (1H, d, J=6.4 Hz),
8.51 (1H, d, J=6.4 Hz), 8.68 (1H, d, J=6.4 Hz), 8.80 (1H, d, J=6.4
Hz), 9,36 (1H, s), 9.40 (1H, s).
EXAMPLE 110
1-[N-(5-Isoquinolinesulfonyl)-N-Methyltyrosyl]-4-Phenylpiperazine
1.15 g of the amorphous compound obtained in Example 109 was
suspended in 20 ml of methanol, to the solution was added 2 ml of
2N sodium hydroxide aqueous solution, and the mixture was refluxed
for 90 minutes. After adding 100 ml of water, the reaction mixture
was extracted twice with 50 ml of chloroform, and the extract was
dried over magnesium sulfate and concentrated under a reduced
pressure. Resulting residue was applied to a silica gel column and
eluted with chloroform/methanol (80:1 to 50:1), to obtain mg of the
title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 :1638, 1590, 1440, 1326 1150;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.56 (1H, dd, J=5.4, 12.7
Hz), 2.61 (1H, m), 2.90-3.22 (3H, m), 3.15 (3H, s), 3.43 (1H, m),
3.51-3.71 (4H, m), 5.13 (1H, dd, J=5.9, 9.8 Hz), 5.53 (1H, br),
6.62 (2H, d, J=8.8 Hz), 6.84 (2H, d, J=7.8 Hz), 6.89 (1H, t, J=7.3
Hz), 6.90 (2H, d, J=8.3 Hz), 7.26 (2H, t, J=7.8 Hz), 7.70 (1H, dd,
J=7.3, 8.3 Hz), 8.21 (1H, d, J=8.3 Hz), 8.32 (1H, dd, J=1.0, 7.3
Hz), 8.38 (1H, d, J=5.9 Hz), 66 (1H, d, J=5.9 Hz), 9.33 (1H,
br).
EXAMPLE 111
The product of Example 108 was subjected to alkaline hydrolysis
according to the procedure described in Example 110 to obtain
1-[N-(5-isoquinolinesulfonyl)tyrosyl]-4-phenylpiperazine in a
yellow amorphous form.
IR (KBr) cm.sup.-1 :1630, 1590, 1510, 1440, 1325, 1220, 1150,
1128;
.sup.1 H-NMR (CDCl.sub.3 -CD.sub.3 OD, .delta. ppm): 2.60 (1H, m),
2.72-2.77 (2H, m), 2.88 (4H, m), 3.10-3.43 (3H, m), 4.37 (1H, t,
J=7.8 Hz), 6.40 (2H, d, J=8.3 Hz), 6.72 (2H, d, J=8.3 Hz), 6.83
(2H, d, J=7.8 Hz), 6.91 (1H, t, J=7.3 Hz), 7.27 (2H, dd, J=7.8, 8.3
Hz), 7.63 (1H, dd, J=7.3, 8.3 Hz), 8.17 (1H, d, J=8.3 Hz), 8.30
(1H, dd, J=1.0, 7.3 Hz), 8.38 (1H, d, J=6.4 Hz), 8.60 (1H, d, J=6.4
Hz), 9.24 (1H, s).
REFERENCE EXAMPLE 25
N-Benzyloxycarbonylhomopiperazine
To 230 ml of dimethylformamide were added 25 g of homopiperazine
and 5.4 g of sodium bicarbonate and then 25 ml of water followed by
dropwise addition of 10 g of benzyloxycarbonyl chloride with
stirring under ice cooling, and the mixture was stirred at a room
temperature overnight. After evaporating off dimethylformamide
under a reduced pressure, the reaction mixture was extracted three
times with 100 ml of chloroform, and the extract was dried over
magnesium sulfate and evaporated to remove the solvent under a
reduced pressure. The resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (9:1), to obtain 9 g of
the title compound as a light yellow liquor liquid.
IR (KBr) cm.sup.-1 :1695, 1420;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8 (2H, m), 2.8-3.0 (4H,
m), 3.4-3.65 (4H, m), 5.15 (2H, s), 7.4 (5H, s).
REFERENCE EXAMPLE 26
1-[N-(Tert-Butoxycarbonyl)-N-Methyl]Tyrosyl-4-Benzyloxycarbonylhomopiperazi
ne
1.0 g of N-tert-butoxycarbonyl-N-methyltyrosine was dissolved in 70
ml of methylene chloride, and after adding 793 mg of
N-benzyloxycarbonylhomopiperazine and adding at a stroke 837 mg of
DCC at a room temperature with stirring, the mixture was stirred at
a room temperature overnight. The solvent was evaporated off under
a reduced pressure, and to the resulting residue was added benzene
Insoluble matter was filtered off, and the filtrate was applied to
a silica gel column and eluted with hexane/ethyl acetate (6:4 to
6:5) to obtain 1.06 g of the title compound as a light yellowish
oil.
Acetylated derivative of this compound has the following
properties.
IR (KBr) cm.sup.-1 :1760, 1695, 1215, 1200;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.3, 1.4 (Total 9H, each
s), 1.85 (1H, m), 2.3 (3H, s), 2.82 (3H, brs), 2.7-2.9 (2H, m),
3.0-3.8 (8H, m), 5.15 (2H, brs), 7.0 (2H, d, J=8.3 Hz), 7.35 (5H,
brs).
REFERENCE EXAMPLE 27
1-{3'-(P-Acetoxyphenyl)-2'-[N-(Tert-Butoxycarbonyl)-N-Methylamino]Propyl}-4
-Benzyloxycarbonylhomopiperazine
3.56 g of the product obtained in Reference Example 26 was
dissolved in 60 ml of absolute tetrahydrofuran, to the solution was
added 20 ml of 1.0M borane in tetrahydrofuran with stirring under
ice cooling, and the mixture was stirred overnight at a room
temperature. The solvent was evaporated off under a reduced
pressure, and resulting residue was dissolved in 10 ml of pyridine.
To the solution was added 5 ml of acetic anhydride, and the mixture
was allowed to stand overnight at a room temperature. After an
addition of ice, the mixture was stirred for 30 minutes and
extracted twice with 60 ml of chloroform. The extract was washed
with saturated sodium chloride aqueous solution, dried over
magnesium sulfate and evaporated to remove the solvent under a
reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (100:1), to obtain 2.0 g
of the title compound in a light yellow amorphous form.
IR (KBr) cm.sup.-1 :1760, 1690, 1215, 1200;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.25, 1.27 (Total 9H, each
s), 1.6-1.9 (2H, m), 2.27 (3H, s), 2.4-2.8 (l1H, m), 3.4-3.6 (4H,
m), 5.13 (2H, brs), 6.97 (2H, d, J=8.6 Hz), 7.1 (2H, d, J=8.6 Hz),
7.25, 7.33 (Total 5H, each s).
EXAMPLE 112
N-[1-(P-Acetoxybenzyl)-2-(4-Benzyloxycarbonylhomopiperazinyl)Ethyl]-N-Methy
l-5-Isoquinolinesulfonamide
1 g of the amorphous compound obtained in Reference Example 27 was
dissolved in 28 ml of methylene chloride, to the solution were
added 2 ml of 2,6-lutidine, and then 2 ml of
tert-butyldimethylsilyltrifluoromethane sulfonate with stirring at
a room temperature, and the reaction mixture was stirred for 16
hours. After an addition of ice, the reaction mixture was extracted
twice with 70 ml of ethyl acetate, and the extract was washed with
saturated sodium chloride aqueous solution, dried over magnesium
sulfate and evaporated to remove the solvent under a reduced
pressure. To resulting residue were added 20 ml of tetrahydrofuran
and 4.28 ml of 1.0M tetrabutylammonium fluoride in tetrahydrofuran
with stirring, and the reaction mixture was stirred at a room
temperature for 40 minutes. After adding ice, the reaction mixture
was extracted twice with 70 ml of chloroform, and the extract was
washed with saturated sodium chloride aqueous solution, dried over
magnesium sulfate and evaporated to remove the solvent under a
reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (95:5 to 90:10), to
obtain 723 mg of
1-[3'-(p-acetoxyphenyl)-2'-(N-methylamino)propyl]-4-benzyloxycarbonylhomop
iperazine.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8 (2H, m), 2.3 (3H, s),
2.48 (3H, d, J=2.0 Hz), 2.35-3.8 (9H, m), 3.4-3.6 (4H, m), 5.1 (2H,
s), 7.0 (2H, d, J=8.5 Hz), 7.2 (2H, brd, J=8.5 Hz), 7.35 (5H,
s).
723 mg of the abovecompound was dissolved in 25 ml of
dimethylformamide, and to the mixture was added 401 mg of
triethylamine and then 564 mg of 5-isoquinolinesulfonyl
chloride.HCl with stirring under ice cooling, and the mixture was
stirred overnight at a room temperature. After adding water, the
reaction mixture was extracted twice with 70 ml of ethyl acetate,
and the extract was washed with saturated sodium chloride aqueous
solution, dried over magnesium sulfate and evaporated to remove the
solvent under a reduced pressure. Resulting residue was applied to
a silica gel column and eluted with chloroform/methanol (100:1) to
obtain 796 mg of the title compound in a light yellow amorphous
form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.7 (2H, m), 2.3 (3H, s),
2.7-2.8 (8H, m), 2.90, 2.91 (Total 3H, each s), 3.3-3.55 (4H, m),
4.1 (1H, m), 5.1 (2H, s), 6.7 (2H, d, J=8.3 Hz), 6.9 (2H, d, J=8.3
Hz), 7.34, 7.36 (Total 5H, each s), 7.53, 7.55 (Total 1H, each t,
J=7.6 Hz), 8.1 (1H, d, J=6.1 Hz), 8.18 (2H, d, J=6.5 Hz), 8.55 (1H,
d, J=6.1 Hz), 9.25 (1H, s).
EXAMPLE 113
N-[2-(4-Benzyloxycarbonylhomopiperazinyl)-1-(P-Hydroxybenzyl)Ethyl-N-Methyl
-5-Isoquinolinesulfonamide
400 mg of the amorphous compound obtained in Example 112 was
dissolved in 10 ml of methanol, to the solution was added 2 ml of
10% sodium hydroxide and the mixture was stirred for 10 minutes.
The reaction mixture was acidified with citric acid aqueous
solution and then alkalized with saturated sodium bicarbonate
aqueous solution, and extracted twice with 50 ml of chloroform. The
extract was dried over magnesium sulfate and evaporated to remove
the solvent under a reduced pressure. The resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(100:2) to obtain 339 mg of the title compound in a colorless
amorphous form.
IR (KBr) cm.sup.-1 : 1700, 1330, 1210, 1150, 1120;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8 (2H, m), 1.37, 1.38
(Total 1H, each dd, J=10.0, 13.8 Hz), 1.55 (1H, dd, J=13.8, 9.8
Hz), 2.75 (4H, m), 2.7-3.0 (2H, m), 3.0 (3H, s), 3.5 (4H, m), 3.8
(1H, m), 5.13 (2H, s), 6.17 (2H, d, J=8.0 Hz), 6.50, 6.51 (Total
2H, each d, J=8.0 Hz), 7.49, 7.50 (total 1H, each t, J=7.7 Hz),
8.03 (1H, d, J=6.1 Hz) 8.13 (1H, d, J=7.8 Hz), 8.23 (1H, d, J=7.1
Hz), 6.43 (1H, d, J=6.1 Hz), 9.24 (1H, s), 7.35 (5H, s).
EXAMPLE 114
220 mg of the amorphous compound obtained in Example 113 was
dissolved in 2 ml of acetic acid, to the solution was added 6 ml of
25% hydrogen bromide in acetic acid, and the mixture was stirred at
a room temperature for 20 minutes. 40 ml of dry ether was added to
the reaction mixture to form a white precipitate, which was then
alkalized with saturated sodium bicarbonate aqueous solution and
extracted twice with 20 ml of chloroform/isopropanol (5:1). The
extract was dried over magnesium sulfate and evaporated to remove
the solvent under a reduced pressure, and resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(20:80 to 30:70) to obtain 67 mg of N-[1-(p-hydroxy)
benzyl-2-homopiperazinylethyl]-N-methyl-5-isoquinolinesulfonamide
as a light yellow oil.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.75 (2H, m), 2.3-3.0 (12H,
m), 2.93 (3H, s), 3.96 (1H, m), 6.3 (2H, d, J=8.3 Hz), 6.6 (2H, d,
J=8.3 Hz), 7.6 (1H, t, J=8.1 Hz), 8.1 (1H, d, J=5.3 Hz), 8.12 (1H,
d, J=8.3 Hz), 8.2 (1H, d, J=7.4 Hz), 8.45 (1H, d, J=6.1 Hz), 9.26
(1H, s).
REFERENCE EXAMPLE 28
1-Benzyloxycarbonyl-4-(N-Tert-Butoxycarbonyltyrosyl)Homopiperazine
15.29 g of N-tert-butoxycarbonyltyrosine and 12.73 g of
N-benzyloxycarbonylhomopiperazine were dissolved in 280 ml of
tetrahydrofuran, to the solution were added 8.09 g of
1-hydroxybenzotriazole hydrate and 11.77 g of DCC at a room
temperature with stirring, and the reaction mixture was stirred for
16 hours. The reaction mixture was evaporated to remove the solvent
under a reduced pressure, to the residue was added benzene, and
insoluble matter was filtered by suction and washed with benzene.
The benzene layers were combined and evaporated off under a reduced
pressure. The resulting residue was applied to a silica gel column
and eluted with chloroform/methanol (100:1), to obtain 26.42 g of
the title compound in colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.41 (9H, s), 1.5-2.0 (2H,
m), 2.75-3.05 (2H, m), 3.05-3.7 (8H, m), 4.67 (1H, m), 5.10, 5.12
(Total 2H, each s), 5.25 (1H, m), 6.0 (1H, br), 6.68, 6.72 (Total
2H, each d, J=8.57 Hz), 7.02, 7.03 (Total 2H, each d, J=8.57 Hz),
7.32, 7.34 (Total 5H, each s).
EXAMPLE 115
N-{2-(4-Benzyloxycarbonyl)Homopiperazinyl]-1-[P-(5-Isoquinolinesulfonyloxy)
Benzyl]Ethyl}-5-Isoquinolinesulfonamide
3.0 g of the amorphous compound obtained in Reference Example 28
was dissolved in 20 ml of tetrahydrofuran, to the solution was
added 24 ml of 1M borane in tetrahydrofuran, and the mixture was
stirred under a nitrogen atmosphere at a room temperature for 15
hours. After the reaction was completed, the solvent was evaporated
off under a reduced pressure and to the resulting residue was added
3 g of potassium bicarbonate. The mixture was stirred for 30
minutes at a room temperature and extracted twice with 200 ml of
chloroform. The extract was dried over magnesium sulfate and
concentrated under a reduced pressure, to obtain
1-benzyloxycarbonyl-4-[2-(tert-butoxycarbonylamino)-3-(p-hydroxyphenyl)pro
pyl]homopiperazine.
This compound was dissolved in 6 ml of ethyl acetate, to the
solution was added 30 ml of 4N hydrogen chloride in ethyl acetate,
and the mixture was stirred at a room temperature for 30 minutes.
The reaction mixture was evaporated under a reduced pressure and
the resulting residue was alkalized with a saturated sodium
bicarbonate aqueous solution and extracted twice with 200 ml of
chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure, to
obtain 2.43 g of 1-[2-amino-3-(p-hydroxyphenyl)propyl]-4-benzyloxy
carbonylhomopiperazine.
This intermediate was dissolved in 65 ml of tetrahydrofuran, to the
solution were added 4.03 g of 5-isoquinolinesulfonyl chloride.HCl
and 8.9 ml of triethylamine at a room temperature with stirring,
and the mixture was stirred for 16 hours. After an addition of a
saturated sodium bicarbonate solution, the mixture was extracted
twice with 300 ml of chloroform, and the extract was dried over
magnesium sulfate and evaporated to remove the solvent under a
reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (20:1), to obtain 2.26 g
of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.43 (2H, m), 2.2 (6H, m),
2 73 (2H, m), 2.9-3.4 (5H, m), 5.07 (2H, s), 5.34 (1H, br), 6.62
(2H, d, J=8.57 Hz), 6.84, 6.86 (Total 2H, each d, J=8.57 Hz), 7.32,
7.33 (Total 5H, each s), 7.63 (1H, t, J=8.28 Hz), 7.67 (1H, m),
8.16 (1H, t, J=8.28 Hz), 7.67 (1H, m), 8.16 (1H, t, J=7.42 Hz), 8
22-8.45 (4H, m), 8.53 (1H, d, J=6.28 Hz), 8.66 (1H, dd, J=6.57, 1.0
Hz), 8.82 (1H, d, J=6.28 Hz), 9.31, 9.34 (Total 1H, each s), 9.42
(1H, s).
EXAMPLE 116
1.0 g of the product obtained in Example 115 was dissolved in 5 ml
of methanol and 5 ml of tetrahydrofuran, to the solution was added
10 ml of 1N sodium hydroxide, and the mixture was refluxed for 2
hours and then cooled. The reaction mixture was acidified with
citric acid and then alkalized with sodium bicarbonate, the
produced insoluble matter, was then dissolved in methanol. The
solution was extracted twice with 100 ml of chloroform, and the
extract was dried over magnesium sulfate and concentrated under a
reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (20:1), to obtain 458 mg
of
N-{2-(4-benzyloxycarbonylhomopiperazinyl)-1-(p-hydroxybenzyl)ethyl}-5-isoq
uinolinesulfonamide in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.72 (2H, brs), 2.3-2.9
(8H, m), 3.1-3.7 (5H, m), 5.12 (2H, s), 6.27 (2H, d, J=7.32 Hz),
6.57 (2H, d, J=7.32 Hz), 7.6 (1H, br), 7.33 (6H, s), 7.63 (1H, t,
J=7.57 Hz), 8.17 (1H, d, J=8.3 Hz), 8.33 (2H, d, J=7.08 Hz), 8.52
(1H, brs), 9.28 (1H, brs).
EXAMPLE 117
N-{1-P-(5-Isoquinolinesulfonyloxy)Benzyl]-2-Homopiperazinylethyl}-5-Isoquin
olinesulfonamide
To 1.0 g of the product obtained in Example 115, was added 6 ml of
30% hydrogen bromide in acetic acid at a room temperature with
stirring, and the mixture was further stirred for 24 hours. After
an addtion of 100 ml of ether the reaction mixture was stirred for
30 minutes to form a salt, which was then colected by filtration,
washed with ether and dried in a desiccator. The salt was dissolved
in water, and the solution was alkalized with sodium bicarbonate
and extracted twice with 100 ml of chloroform. The extract was
dried with magnesium sulfate and evaporated to remove the solvent
under a reduced pressure, to obtain 830 mg of the title compound in
a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.37 (2H, m), 2.1-2.9 (12H,
m), 3.22 (1H, m), 6.62 (2H, d, J=8.79 Hz), 6.87 (2H, d, J=8.54 Hz),
7.64 (1H, t, J=7.82 Hz), 7.66 (1H, t, J=7.82 Hz), 8.18 (1H, d,
J=8.31 Hz), 8.23-8.36 (3H, m), 8.40 (1H, d, J=6.35 Hz), 8.53 (1H,
d, J=6.1 Hz), 8.67 (1H, d, J=6.11 Hz), 8.81 (1H, d, J=6.35 Hz),
9.33 (1H, s), 9.42 (1H, s).
EXAMPLE 118
N-{1-[P-(5-Isoquinolinesulfonyloxy)Benzyl]-2-[4-(3-Phenylpropionyl)Homopipe
razinyl]Ethyl}-5-Isoquinolinesulfonamide
420 mg of the amorphous compound obtained in Example 117 was
dissolved in 6 ml of methylene chloride, to the solution were added
125 mg of 3-phenylpropionyl chloride and 100 mg of triethylamine at
a room temperature with stirring, and the mixture was stirred for
17 hours. The reaction mixture was alkalized with a saturated
sodium bicarbonate aqueous solution and extracted twice with 50 ml
of chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent. Resulting residue was applied to
a silica gel column and eluted with chloroform/methanol (30:1) to
obtain 400 mg of the title compound in colorless amorphous
form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.46 (2H, m), 1.9-2.4 (6H,
m), 2.4-2.6 (2H, m), 2.6-2.82 (2H, m), 2.82-2.98 (2H, m), 2.98-3.12
(1H, m), 3.12-3.33 (3H, m), 3.4 (1H, t, J=6.28 Hz), 6.61, 6.63
(Total 2H, each d, J=8.57 Hz), 6.82, 6.85 (Total 2H, each d, J=8.57
Hz), 7.1-7.35 (5H, m), 7.64 (1H, t, J=8.28 Hz), 7.66 (1H, t, J=8.28
Hz), 8.1-8.45 (5H, m), 8.52 (1H, d, J=6.28 Hz), 8.67 (1H, dd,
J=6.28, 1.0 Hz), 8.82 (1H, d, J=6.28 Hz), 9.33, 9.34 (Total 1H,
each s), 9.42 (1H, s).
EXAMPLE 119
N-{1-(P-Hydroxybenzyl)-2-[4-(3-Phenylpropionyl)Homopiperazinyl]Ethyl}-5-Iso
quinolinesulfonylamide
400 mg of the amorphous compound obtained in Example 118 was
dissolved in 2 ml of methanol and 2 ml of tetrahydrofuran, to the
solution was added 4 ml of 1N sodium hydroxide, and the mixture was
refluxed for 3 hours and then cooled. The reaction mixture was
acidified with citric acid and then alkalized with sodium
bicarbonate to form an insoluble matter, which was then dissolved
in a small amount of methanol and extracted twice with 50 ml of
chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure.
Resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (30:1), to obtain 230 mg of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.64 (2H, m), 2.3-2.85
(10H, m), 2.96 (2H, t, J=8.3 Hz), 3.15-3.6 (5H, m), 6.31, 6.35
(Total 2H, each d, J=8.30 Hz), 6.57, 6.61 (Total 2H, each d, J=8.30
Hz), 7.1-7.4 (5H, m), 7.65 (1H, t, J=8.06 Hz), 8.19 (1H, d, J=8.23
Hz), 8.25-8.4 (2H, m), 8.55 (1H, d, J=6.28 Hz), 9.32 (1H, s).
REFERENCE EXAMPLE 29
1-Benzyloxycarbonyl-4-(N-Tert-Butoxycarbonyl-O-Methyl)Tyrosylhomopiperazine
5.0 g of the amorphous compound obtained in Reference Example 28
was dissolved in 25 ml of tetrahydrofuran and 25 ml of
dimethylformamide, to the solution was added 0.41 g of 60% sodium
hydride with stirring under ice cooling, and then the mixture was
allowed to warm to a room temperature and stirred for 30 minutes.
After adding 1.43 g of methyl iodide, the reaction mixture was
stirred for 16 hours, and after an addition of a saturated sodium
chloride aqueous solution, extracted twice with 300 ml of
chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure.
Resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1), to obtain 3.76 g of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.41 (9H, s), 1.65-2.0 (2H,
m), 2.8-3.05 (2H, m), 3.05-3.65 (8H, m), 3.77 (3H, s), 5.68 (1H,
m), 5.10 (2H, s), 5.23 (1H, m), 6.79 (2H, d, J=8.3 Hz), 7.11 (2H,
d, J=8.54 Hz), 7.33 (5H, s).
REFERENCE EXAMPLE 30
1-(N-Tert-Butoxycarbonyl-O-Methyl)Tyrosyl-4-Phenylacetylhomopiperazine
1.02 g of the amorphous compound obtained in Reference Example 29
was dissolved in 25 ml of methanol, to the solution was added 250
mg of 5% palladium on carbon with ice cooling, and after warming
the mixture to a room temperature, the catalytic reduction was
carried out for 6 hours. The catalyst was filtered off and washed
with methanol, and the methanol solution was evaporated to obtain
800 mg of
(N-tert-butoxycarbonyl-o-methyl)tyrosylhomopiperazine.
400 mg of the compound was dissolved in 6 ml of methylene chloride,
to the solution were added 195 mg of phenylacetyl chloride and 190
mg of triethylamine, and the mixture was stirred at a room
temperature for 24 hours. The reaction mixture was alkalized with a
saturated sodium bicarbonate aqueous solution and extracted twice
with 100 ml of chloroform, and the extract was dried over magnesium
sulfate and evaporated to remove the solvent under a reduced
pressure. Resulting residue was applied to a silica gel column and
eluted with chloroform/methanol (50:1), to obtain 433 mg of the
title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.41 (9H, s), 1.6-2.0 (2H,
m), 2.7-3.75 (12H, m), 3.77, 3.78 (Total 3H, each s), 4.65 (1H, m),
5.13, 5.24 (Total 1H, each d, J=9.14 Hz), 6.78, 6.79 (Total 2H,
each d, J=9.71 Hz), 7.08, 7.11 (Total 2H, each d, J=9.71 Hz), 7.28
(5H, m).
EXAMPLE 120
1-[N-(5-Isoquinolinesulfonyl)-O-Methyl]Tyrosyl-4-Phenylacetylhomopiperazine
433 mg of the amorphous compound obtained in Reference Example 30
was dissolved in 1 ml of ethyl acetate, to the solution was added 4
ml of 4N hydrogen chloride in ethyl acetate, and after stirring for
30 minutes at a room temperature, the solvent was evaporated off
under a reduced pressure. To resulting residue was added a
saturated sodium bicarbonate aqueous solution, and the solution was
twice extracted with 50 ml of chloroform. The extract was dried
over magnesium sulfate and concentrated under a reduced pressure.
To resulting residue were added 6 ml of tetrahydrofuran, as well as
275 mg of 5-isoquinolinesulfonyl chloride.HCl and 1.2 ml of
triethylamine at a room temperature with stirring, and the mixture
was further stirred for 18 hours. The reaction mixture was
alkalized with a saturated sodium bicarbonate aqueous solution and
extracted twice with 50 ml of chloroform, and the extract was dried
over magnesium sulfate and evaporated to remove the solvent under a
reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (30:1), to obtain 439 mg
of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5-1.9 (2H, m), 2.4-2.9
(3H, m), 2.9-4.0 (9H, m), 3.67, 3.68, 3.70 (Total 3H, each s), 4.18
(1H, m), 6.18 (1H, m), 6.25-6.5 (2H, m), 6.7 (2H, m), 7.28 (5H, m),
7.54, 7.56 (Total 1H, each t, J=7.81 Hz), 8.09 (1H, t, J=7.81 Hz),
8.15-8.3 (2H, m), 8.63 (1H, m), 9.22, 9.26 (Total 1H, each s).
EXAMPLE 121
1-[N,O-Dimethyl-N-(5-Isoquinolinesulfonyl)]Tyrosyl-4-Phenylacetylhomopipera
zine
439 mg of the amorphous compound obtained in Example 120 was
dissolved in 2.5 ml of tetrahydrofuran and 2.5 ml of
dimethylformamide, to the solution was added 30 mg of 60% sodium
hydride with ice cooling, and then the mixture was warmed to a room
temperature and stirred for 30 minutes. After an addition of 110 mg
of methyl iodide, the reaction mixture was further stirred for 16
hours. After an addition of a saturated sodium chloride aqueous
solution, the reaction mixture was extracted twice with 50 ml of
chloroform, and the extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure.
Resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (30:1), to obtain 348 mg of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5-2.0 (2H, m), 2.2-4.0
(12H, m), 3.03, 3.07, 3.08, 3.19 (Total 3H, each s), 3.71, 3.73,
3.75 (Total 3H, each s), 4.9 (1H, m), 6.5-6.78 (2H, m), 6.78-7.0
(2H, m), 7.26 (5H, m), 7.68 (1H, m), 8.1-8.33 (2H, m), 8.42 (1H,
m), 8.66 (1H, m), 9.32 (1H, m).
EXAMPLE 122
1-Benzyloxycarbonyl-4-[N,O-Bis(5-Isoquinolinesulfonyl)Tyrosyl]Homopiperazin
e
6.44 g of the amorphous compound obtained in Reference Example 28
was dissolved in 6 ml of ethyl acetate, to the solution was added
60 ml of 4N hydrogen chloride in ethyl acetate at a room
temperature with stirring, and the mixture was stirred for 3 hours.
The reaction mixture was concentrated under a reduced pressure and
after an addition of benzene, again concentrated under a reduced
pressure, to obtain
1-benzyloxycarbonyl-4-tyrosylhomopiperazine/hydrochloride in an
amorphous form.
To this intermediate were added 130 ml of tetrahydrofuran as well
as 7.88 g of 5-isoquinolinesulfonyl chloride.HCl and 18 ml of
triethylamine, and the mixture was stirred for 18 hours at a room
temperature. The reaction mixture was alkalized with a saturated
sodium bicarbonate aqueous solution and extracted twice with 700 ml
of chloroform, and the extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure.
Resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (30:1) to obtain 5.50 g of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.65 (2H, m), 2.4-3.8 (10H,
m), 4.17 (1H, m), 5.1 (2H, m), 6.02 (1H, d, J=9.52 Hz), 6.47, 6.51
(Total 2H, each d, J=8.55 Hz), 6.75 (2H, d, J=8.55 Hz), 7.29, 7.33
(Total 5H, each s), 7.58, 7.60 (Total 1H, each t, J=8.06 Hz),
8.1-8.3 (5H, m), 8.52 (1H, d, J=6.11 Hz), 8.64 (1H, d, J=6.10 Hz),
8.84 (1H, d, J=5.37 Hz), 9.29 (1H, s), 9.41 (1H, s).
EXAMPLE 123
1-Benzyloxycarbonyl-4-[N-(5-Isoquinolinesulfonyl)Tyrosyl]Homopiperazine
5.50 g of the amorphous compound obtained in Example 122 was
dissolved in 30 ml of methanol and 30 ml of tetrahydrofuran, to the
solution was added 60 ml of 1N sodium hydroxide, and the mixture
was refluxed for 2 hours and then cooled. The reaction mixture was
acidified with citric acid and then alkalized with sodium
bicarbonate, resulting insoluble matter was dissolved with a small
amount of methanol, and the solution was extracted twice with 400
ml of chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (20:1) to obtain 3.1 g of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3 +DC.sub.3 OD, .delta. ppm): 1.82 (2H, m),
2.48 (1H, m), 2.68 (1H, dt, J=6.85, 5.71 Hz), 3.1-3.8 (8H, m), 4.16
(1H, m), 5.12, 5.13 (Total 2H, each s), 6.14, 6.17 (Total 2H, each
d, J=8.55 Hz), 6.52, 6.53 (Total 2H, each d, J=8.55 Hz), 7.33, 7.35
(Total 5H, each s), 7.61 (1H, m), 8.16 (1H, d, J=8.06 Hz), 8.2-8.45
(2H, m), 8.53 (1H, d, J=6.11 Hz), 9.21 (1H, s).
REFERENCE EXAMPLE 31
N-Benzyloxycarbonyltyrosine and N-tert-butoxycarbonylhomopiperazine
were treated according to the procedure in Reference Example 28 to
obtain
1-(N-benzsyloxycarbonyl)tyrosyl-4-tert-butoxycarbonylhomopiperazine
in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.42, 1.44 (Total 9H, each
s), 1.6-2.0 (2H, m), 2.7-3.8 (10H, m), 4.75 (1H, m), 5.04 (1H, d,
J=11.42 Hz), 5.13 (1H, d, J=11.42 Hz), 5.5 (1H, m), 6.72 (2H, m),
7.02 (2H, m), 7.34 (5H, s).
REFERENCE EXAMPLE 32
1-(O-Acetyl-N-Benzyloxycarbonyl)Tyrosyl-4-Tert-Butoxycarbonylhomopiperazine
690 mg of the amorphous compound obtained in Reference Example 31
was dissolved in 7 ml of pyridine, and to the solution was added
3.5 ml of acetic anhydride at a room temperature with stirring, and
the mixture was further stirred for 18 hours. After pouring the
reaction mixture to saturated sodium hydroxide aqueous solution to
alkalize, the mixture was extracted twice with 100 ml of
chloroform. The extract was washed with a saturated sodium chloride
aqueous solution, dried over magnesium sulfate, and evaporated to
remove the solvent under a reduced pressure. Resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(100:1) to obtain 670 mg of the title compound in a colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.41, 1.43 (Total 9H, each
s), 1.5-2.0 (2H, m), 2.28 (3H, s), 2.8-3.7 (10H, m), 4.7 (1H, m),
5.05 (1H, d, J=11.4 Hz), 5.13 (1H, d, J=11.4 Hz), 5.52 (1H, m),
6.99 (2H, d, J=7.42 Hz), 7.21 (2H, d, J=7.42 Hz), 7.34 (5H, s).
REFERENCE EXAMPLE 33
1-(O-Acetyl-N-Benzyloxycarbonyl)Tyrosyl-4-(3-Phenylpropyl)Homopiperazine
670 mg of the amorphous compound obtained in reference Example 32
was dissolved in 2 ml of ethyl acetate, and to the solution was
added 7 ml of 3N hydrogen chloride in ethyl acetate at a room
temperature with stirring, and the mixture was further stirred for
30 minutes, alkalized with sodium bicarbonate aqueous solution,
saturated with sodium chloride, and extracted twice with 100 ml of
ethyl acetate. The extract was dried over magnesium sulfate and
evaporated under a reduced pressure, to obtain 460 mg of
1-(O-acetyl-N-benzyloxycarbonyl)tyrosylhomopiperazine.
This compound was dissolved in 6 ml of dimetylformamide, and to the
solution were added 150 mg of potassium carbonate, 160 mg of sodium
iodide and 210 mg of 1-bromo-3-phenylpropane at a room temperature
with stirring, and the mixture was stirred for 20 hours. After an
addition of a saturated sodium chloride aqueous solution, the
reaction mixture was extracted twice with 100 ml of chloroform, and
the extract was dried over magnesium sulfate and evaporated to
remove the solvent under a reduced prssure. Resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(100:1) to obtain 430 mg of the title compound in a colorless
amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5-2.0 (6H, m), 2.26 (3H,
s), 2.3-2.7 (6H, m), 2.9-3.8 (6H, m), 4.84 (1H, m), 5.03 (1H, d,
J=11.99 Hz), 5.12 (1H, d, J=11.99 Hz), 5.6 (1H, m), 6.97 (2H, dd,
J=8.57, 1.0 Hz), 7.1-7.3 (7H, m), 7.33 (5H, s).
REFERENCE EXAMPLE 34
1-(3-Phenylpropyl)-4-Tyrosylhomopiperazine
430 mg of the amorphous compound obtained in Reference Example 33
was dissolved in 5 ml of methanol, to the solution was added 120 mg
of potassium carbonate at a room temperature with stirring, and the
reaction mixture was stirred for 70 hours. After an addition of a
saturated sodium chloride aqueous solution, the reaction mixture
was acidified with citric acid and extracted twice with 100 ml of
chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure.
Resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1) to obtain 395 mg of
1-(N-benzyloxycarbonyl)tyrosyl-4-(3-phenylpropyl)homopiperazine.
This compound was dissolved in 15 ml of methanol, and to the
solution were added 0.05 ml of concentrated hydrochloric acid and
150 mg of 5% palladium on carbon with ice cooling. After warming
the reaction mixture to a room temperature, the catalytic reduction
was carried out in a hydrogen atmosphere for 8 hours. The palladium
on carbon catalyst was filtered by suction, and washed with
methanol The filtrates were combined and evaporated to remove the
solvent under a reduced pressure, and to resulting residue was
added saturated sodium chloride aqueous solution The mixture was
alkalized with a sodium bicarbonate aqueous solution, precipitated
insoluble matter was dissolved by adding a small amount of
methanol, and the mixture was extracted twice with 80 ml of
chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (20:1), to obtain 180 mg of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.75 (4H, m), 2.3-2.8 (10H,
m), 2.92 (1H, m), 3.1-3.8 (4H, m), 3.86 (1H, q, J=6.28 Hz), 6.65,
6.66 (Total 2H, each d, J=8.57 Hz), 6.99, 7.00 (Total 2H, each d,
J=8.57 Hz), 7.1-7.35 (5H, m).
EXAMPLE 124
1-[N-(5-Isoquinolinesulfonyl)Tyrosyl]-4-(3-Phenylpropyl)Homopiperazine
180 mg of the amorphous compound obtained in Reference Example 34
was dissolved in 4 ml of tetrahydrofuran, and to the solution were
added 137 mg of 5-isoquinolinesulfonyl chloride.HCl and 0.2 ml of
triethylamine at a room temperature with stirring, and the mixture
was stirred for 15 hours. After an addition of a saturated sodium
chloride aqueous solution, the reaction mixture was alkalized with
sodium bicarbonate, and the precipitated insoluble matter was made
oily by adding a small amount of methanol, and the mixture was
extracted twice with 50 ml of chloroform. The extract was dried
over magnesium sulfate and evaporated to remove the solvent under a
reduced pressure. Resulting residue was applied to a silica gel
column and a preparative thin layer chromatographic plate and
eluted with chloroform/methanol (10:1), to obtain 130 mg of the
title compound in colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3 +CD.sub.3 OD, .delta. ppm): 1.76 (4H, m),
2.3-2.8 (10H, m), 3.1-3.7 (4H, m), 4.22 (1H, m), 6.17, 6.19 (Total
2H, each d, J=8.57 Hz), 6.53, 6.56 (Total 2H, each d, J=8.57 Hz),
7.1-7.4 (5H, m), 7.57, 7.59 (Total 1H, each t, J=8.28 Hz), 8.12
(1H, d, J=8.28 Hz), 8.15-8.35 (2H, m), 8.53 (1H, dd, J=6.28, 1.0
Hz), 9.18 (1H, s).
EXAMPLE 35
1-[N-(Tert-Butoxycarbonyl)-P-Nitrophenylalanyl]-4-(P-Methoxyphenyl)Piperazi
ne
9.00 g of N-(tert-butoxycarbonyl)-p-nitrophenylalanine was
dissolved in 120 ml of tetrahydrofuran, 100 ml of methylene
chloride and 100 ml of chloroform, and to the solution were
sequentially added 7.68 g of N-(p-methoxyphenyl) piperazine
dihydrochloride and 4.44 g of N-hydroxybenzotriazole monohydrate as
well as 20 ml of triethylamine and 6 g of DCC, and the mixture was
stirred at a room temperature for 18 hours. The reaction mixture
was concentrated to one third of the original volume under a
reduced pressure, and after adding 200 ml of 2.5% potassium
carbonate aqueous solution, extracted twice with 200 ml of
chloroform. The extract was dried over magnesium sulfate and
concentrated under a reduced pressure to crystallize a product,
which was washed with methanol to obtain 10.75 g of the title
compound as colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.40 (9H, s), 2.73 (1H, m),
2.87-3.00 (3H, m), 3.04 (1H, dd, J=6.3, 13.2 Hz), 3.17 (1H, dd,
J=7.3, 13.2 Hz), 3.35 (1H, m), 3.55-3.70 (2H, m), 3.77 (3H, s),
3.84 (1H, m), 4.92 (1H, m), 5.4 (1H, d, J=8.8 Hz), 6.83 (4H, s),
7.38 (2H, d, J=8.8 Hz), 8.16 (2H, d, J=8.8 Hz).
REFERENCE EXAMPLE 36
1-N-(Tert-Butoxycarbonyl)-P-Aminophenylalanyl]-4-(P-Methoxyphenyl)Piperazin
e
10.75 g of the crystals obtained in Reference Example 35 was
dissolved in a mixed solvent of 100 ml of tetrahydrofuran and 20 ml
of methanol, and to the solution was added 5 g of 5% palladium on
carbon, and the mixture was stirred for 2 hours at a room
temperature in a hydrogen atmosphere. After filtering off insoluble
matter, the filtrate was concentrated under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (200:1 to 100:1), to obtain 10.08 g of the
title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.43 (9H, s), 2.42 (1H, m),
2.75-3.00 (4H, m), 3.13 (1H, m), 3.43 (1H, m), 3.57 (1H, m),
3.63-3.73 (2H, m), 3.76 (3H, s), 4.78 (1H, m), 5.43 (1H, br), 6.59
(2H, d, J=8.3 Hz), 6.82 (4H, s), 6.98 (2H, d, J=8.3 Hz).
REFERENCE EXAMPLE 37
1-[3-(P-Aminophenyl)-2-(Tert-Butoxycarbonylamino)Propyl]-4-(P-Methoxyphenyl
)Piperazine
2.54 g of lithium aluminum hydride was suspended in 75 ml of
tetrahydrofuran, to the suspension was added a solution of 8.91 g
of aluminum chloride in 75 ml of ether with ice cooling, and also a
solution of 10.08 g of the amorphous compound obtained in Reference
Example 36 in 100 ml of tetrahydrofuran was added dropwise for 20
minutes with ice cooling. Under the same condition the mixture was
stirred for one hours, and after terminating the reaction by adding
a small amount of water, 70 ml of 30% potassium carbonate aqueous
solution and 200 ml of chloroform were added to the reaction
mixture, which was then filtered to remove insoluble matter using
silica gel as a filter aid. The insoluble matter was washed with
20% methanol in chloroform, and the filtrates were combined and
concentrated under a reduced pressure. 200 ml of saturated sodium
bicarbonate aqueous solution was added to the residue, the mixture
was extracted twice with 100 ml of chloroform, and the extract was
dried over magnesium sulfate and concentrated under a reduced
pressure. Resulting residue was applied to a silica gel column and
eluted with chloroform/methanol (100:1) to obtain 7.72 g of the
title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.43 (9H, s), 2.30 (2H, d,
J=6.8 Hz), 2.48-2.68 (4H, m), 2.78 (2H, t, J=6.3 Hz), 3.06 (4H, t,
J=4.9 Hz), 3.76 (3H, s), 3.86 (1H, m), 4.59 (1H, br), 6.62 (2H, d,
J=8.3 Hz), 6.82 (2H, d, J=9.3 Hz), 6.89 (2H, d, J=9.3 Hz), 6.98
(2H, d, J=8.3 Hz).
REFERENCE EXAMPLE 38
1-[2-(Tert-Butoxycarbonylamino)-3-(P-Phthalimidephenyl)Propyl-4-(P-Methoxyp
henyl)Piperazine 7.0 g of the amorphous compound obtained in
Reference Example 37 was dissolved in 70 ml of chloroform, to the
solution was added 2.66 g of phthalic anhydride. The mixture was
refluxed for one hour, concentrated under a reduced pressure, and
after an addition of 100 ml of toluene, further refluxed for 2
hours The solvent was evaporated off under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1 to 50:1), to obtain 8.91 g of the
title compound as colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.45 (9H, s), 2.37 (2H, d,
J=6.8 Hz), 2.51-2.71 (4H, m), 2.96 (2H, d, J=5.4 Hz), 3.09 (4H, t,
J=4.9 Hz), 3.77 (3H, s), 4.01 (1H, m), 4.66 (1H, br), 6.83 (2H, d,
J=9.3 Hz), 6.90 (2H, d, J=9.3 Hz), 7.36 (4H, s), 7.79 (2H, dd,
J=3.4, 5.4 Hz), 7.96 (2H, dd, J=3.4, 5.4 Hz).
EXAMPLE 125
N-{2-[4-(P-Methoxyphenyl)Piperazinyl]-1-(P-Phthalimidebenzyl)ethyl}-5-isoqu
inolinesulfonamide
8.91 g of the crystals obtained in Reference Example 38 was
dissolved in 50 ml of ethyl acetate, to the solution was added 100
ml of 4N hydrogen chloride in ethyl acetate, and the mixture was
stirred at a room temperature for 1 hour. The reaction mixture was
concentrated under a reduced pressure, and to the residue was added
200 ml of saturated sodium bicarbonate aqueous solution, and the
mixture was extracted twice with 100 ml of 20% methanol/chloroform.
The extract was dried over magnesium sulfate and concentrated under
a reduced pressure to crystallize an amino-free compound. The
crystals was suspended in 120 ml of tetrahydrofuran, to the
suspension were added 5.0 g of 5-isoquinolinesulfonyl chloride.HCl
and 20 ml of triethylamine with ice cooling, and after warming to a
room temperature, the mixture was stirred for 2 hours. After adding
ml of water, formed crystals was collected. The filtrate was
extracted twice with 100 ml of chloroform, and the extract was
dried over magnesium sulfate and concentrated to dryness under a
reduced pressure to obtain a residue. The residue with the crystals
was sequentially washed with methanol, ethyl acetate and hexane to
obtain 6.49 g of the title compound as colorless crystals.
Melting point: 204.degree.-211.degree. C. (decomposed);
IR (KBr) cm.sup.-1 : 1710, 1510, 1370, 1235, 1150, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.03-2.33 (6H, m),
2.46-2.59 (2H, m), 2.59-2.72 (2H, m), 2.85 (1H, dd, J=7.3, 13.7
Hz), 3.10 (1H, dd, J=4.4, 13.7 Hz), 3.41 (1H, m), 3.77 (3H, s),
5.63 (1H, br), 6.73 (2H, d, J=9.3 Hz), 6.83 (2H, d, J=9.3 Hz), 7.20
(2H, d, J=8.8 Hz), 7.29 (2H, d, J=8.8 Hz), 7.74 (1H, t, J=8.3 Hz),
7.80 (2H, dd, J=3.4, 5.4 Hz), 7.96 (2H, dd, J=3.4, 5.4 Hz), 8.24
(1H, d, J=8.3 Hz), 8.48-8.52 (2H, m), 8.72 (1H, d, J=6.4 Hz), 9.36
(1H, s).
EXAMPLE 126
N-{2-[4-(P-Methoxyphenyl)Piperazinyl]-1-(P-Phthalimidebenzyl)Ethyl}-N-Methy
l- 5-Isoquinolinesulfonamide
4.71 g of the crystals obtained in Example 125 was dissolved in 70
ml of dimethylformamide, to the solution were sequentially added
500 mg of 60% sodium hydride and 1 ml of methyl iodide with ice
cooling, and the mixture was stirred under the same condition for 3
hours. The reaction was terminated by adding a small amount of
water, and after adding 200 ml of saturated ammonium chloride
aqueous solution, the mixture was extracted twice with 100 ml of
chloroform. The extract was dried over magnesium sulfate and
concentrated under a reduced pressure. To resulting residue were
added 50 ml of acetic anhydride and 1.2 g of sodium acetate, and
the mixture was stirred for one hour at 80.degree. C. and then
concentrated to dryness under a reduced pressure, and resulting
residue was dissolved in 200 ml of ethyl acetate. The solution was
sequentially washed with 100 ml of saturated sodium bicarbonate
aqueous solution and 100 ml of saturated sodium chloride aqueous
solution, dried over magnesium sulfate, and concentrated under a
reduced pressure. Resulting residue was applied to a silica gel
column and eluted with chloroform/methanol (100:1) to obtain 4.84 g
of the title compound as colorless crystals.
Melting point: 170.degree.-172.degree. C.;
IR (KBr) cm.sup.-1 : 1710, 1610, 1510, 1375, 1300, 1235, 1145,
1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.48 (1H, dd, J=7.3, 13.2
Hz), 2.50-2.63 (4H, m), 2.66 (1H, dd, J=7.3, 13.2 Hz), 2.82 (1H,
dd, J=6.8, 14.2 Hz), 2.86-2.96 (4H, m), 2.97 (3H, s), 3.02 (1H, dd,
J=6.8, 14.2 Hz), 3.77 (3H, s), 4.32 (1H, m), 6.84 (4H, s), 7.15
(2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz), 7.61 (1H, t, J=7.3 Hz),
7.81 (2H, dd, J=2.9, 5.4 Hz), 7.97 (2H, dd, J=2.9, 5.4 Hz), 8.13
(1H, d, J=8.3 Hz), 8.31 (2H, d, J=6.4 Hz), 8.60 (1H, d, J= 6.3 Hz),
9.23 (1H, s).
EXAMPLE 127
1.5 g of the crystals obtained in Example 125 was suspended in 30
ml of ethanol, to the suspension was added 3 ml of hydrozine
hydrate, and the mixture was refluxed for one hour. After adding
10% sodium hydroxide aqueous solution, the reaction mixture was
extracted twice with 30 ml of chloroform. The extract was dried
over magnesium sulfate and concentrated under reduced pressure to
form crystals, which was washed with a mixed solvent of ethyl
acetate and methanol, to obtain 1.14 g of
N-{1-(p-aminovenzyl)-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-5-isoquinoli
nesulfonamide as light yellow crystals.
Melting point: 210.degree.-211.degree. C.;
IR (KBr) cm.sup.-1 : 1615, 1510, 1330, 1245, 1225, 1150, 1130,
1025;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.12-2.34 (6H, m),
2.53-2.72 (5H, m), 2.85 (1H, dd, J=4.9, 14.2 Hz), 3.31 (1H, m),
3.52 (2H, br), 3.77 (3H, s), 5.48 (1H, br), 6.43 (2H, d, J=8.3 Hz),
6.75 (2H, d, J=9.3 Hz), 6.77 (2H, d, J=8.3 Hz), 6.83 (2H, d, J=9.3
Hz), 7.70 (1H, t, J=7.8 Hz), 8.20 (1H, d, J=8.3 Hz), 8.44 (1H, d,
J=6.4 Hz), 8.47 (1H, dd, J=1.0, 7.3 Hz), 8.68 (1H, d, J=6.4 Hz),
9.35 (1H, s).
EXAMPLE 128
4.64 g of the crystals obtained in Example 126 was suspended in 80
ml of ethanol, to the suspension 8 ml of hydrazine hydrate was
added, and the mixture was refluxed for 90 minutes. After adding
100 ml of 10% sodium hydroxide, the reaction mixture was
extracted
over magnesium sulfate and concentrated under a reduced pressure.
Resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1 to 50:1), to obtain 3.29 g of
N-{1-(p-aminobenzyl)-2-[4-(p-methoxyphenyl)piperazinyl]ethyl}-N-methyl-5-i
soquinolinesulfonamide in a yellow amorphous form.
IR (KBr) cm.sup.-1 : 1620, 1510, 1315, 1235, 1150, 1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.43 (1H, dd, J=6.8, 3.2
Hz), 2.53-2.66 (6H, m), 2.85 (1H, dd, J=6.4, 14.2 Hz), 2.87-2.94
(4H, m), 2.92 (3H, s), 3.50 (2H, br), 3.77 (3H, s), 4.20 (1H, m),
6.34 (2H, d, J=8.3 Hz), 6.75 (2H, d, J=8.3 Hz), 6.84 (4H, s), 6.56
(1H, t, J=7.3 Hz), 8.09 (1H, d, J=8.3 Hz), 8.24 (1H, J=6.3 Hz),
8.31 (1H, dd, J=1.0, 7.3 Hz), 8.56 (1H, d, J=5.9 Hz), 9.25 (1H, d,
J=1.0 Hz).
EXAMPLE 129
500 mg of the amorphous compound obtained in Example 128 was
dissolved in 5 ml of pyridine, to the solution was added 305 mg of
5-isoquinolinesulfonyl chloride.HCl under ice cooling, and the
mixture was stirred under the same condition for 20 minutes and
then at a room temperature for one hour. After adding 30 ml of
saturated sodium bicarbonate aqueous solution, the reaction mixture
was extracted twice with 20 ml of chloroform, and the extract was
dried over magnesium sulfate and concentrated under a reduced
pressure. Resulting residue was applied to a silica gel column and
eluted with chloroform/methanol (50:1), to obtain 665 mg of
N-{1-[p-(5-isoquinolinesulfonylaminobenzyl)]-2-[4-(p-methoxyphenyl)piperaz
inyl]ethyl}-N-methyl-5-isoquinolinesulfonamide in a yellow
amorphous form.
IR (KBr) cm.sup.-1 : 1615, 1510, 1325, 1225, 1150, 1130;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.34 (1H, dd, J=7.3, 12.7
Hz), 2.45-2.61 (6H, m), 2.79-2.94 (5H, m), 2.90 (3H, s), 3.77 (2H,
s), 4.04 (1H, m), 6.55 (2H, d, J=8.3 Hz), 6.70 (2H, d, J=8.3 Hz),
6.83 (4H, s), 7.57 (2H, t, J=7.8 Hz), 8.08-8.15 (3H, m), 8.28-8.35
(2H, m), 8.40 (1H, d, J=6.4 Hz), 8.50 (1H, d, J=5.3 Hz), 8.64 (1H,
d, J=6.4 Hz), 9.29 (1H, s), 9.31 (1H, d, J=1.0 Hz).
EXAMPLE 130
200 mg of the crystals obtained in Example 127 was dissolved in 3
ml of pyridine, to the solution was added 130 mg of
5-isoquinolinesulfonyl chloride.1/2 sulfate with ice cooling, and
the mixture was stirred with ice cooling for 20 minutes and then at
a room temperature for one hour, and after adding 30 ml of
saturated sodium bicarbonate aqueous solution, extracted twice with
20 ml of chloroform. The extract was dried over magnesium sulfate
and concentrated under a reduced pressure, and resulting residue
was applied to a silica gel column and eluted with
chloroform/methanol (50:1 to 25:1), to obtain 270 mg of
N-{1-[p-(5-isoquinolinesulfonylaminobenzyl)]-2-[4-(p-methoxyphenyl]piperaz
inyl]ethyl}-5-isoquinolinesulfonamide in a yellow amorphous
form.
IR (KBr) cm.sup.-1 : 1615, 1505, 1330, 1230, 1150, 1125;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.16-2.33 (6H, m),
2.49-2.81 (6H, m), 3.28 (1H, m), 3.76 (3H, s), 6.69 (2H, d, J=8.3
Hz), 6.73 (2H, d, J=9.3 Hz), 6.79 (2H, d, J=8.3 Hz), 6.82 (2H, d,
J=9.8 Hz), 7.61 (1H, t, J=7.8 Hz), 7.67 (1H, t, J=7.8 Hz), 8.16
(1H, d, J=8.3 Hz), 8.19 (1H, d, J=8.3 Hz), 8.34-8.48 (4H, m), 8.62
(2H, d, J=6.4 Hz), 9.33 (1H, s), 9.35 (1H, s).
EXAMPLE 131
N-[[1-{P-[N-5-Isoquinolinesulfonyl)-N-(Methylamino)Benzyl]}-2-[4-(P-Methoxy
phenylpiperazinyl]Ethyl]]-N-Methyl-5-Isoquinolinesulfonamide
503 mg of the amorphous compound obtained in Example 129 was
dissolved in 8 ml of dimethylformamide, to the solution were added
50 mg of 60% sodium hydride and 0.1 ml of methyl iodide with ice
cooling, and the mixture was stirred for one hours with ice
cooling. After adding 30 ml of saturated sodium chloride aqueous
solution, the reaction mixture was extracted with 30 ml of ethyl
acetate, and the extract was washed with a saturated sodium
chloride aqueous solution, dried over magnesium sulfate and
concentrated under a reduced pressure. Resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(100:1), to obtain 488 mg of the title compound in a yellow
amorphous form.
IR (KBr) cm.sup.-1 : 1610, 1505, 1340, 1320, 1235, 1145, 1125,;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.32 (1H, dd, J=6.4, 13.2
Hz), 2.41-2.56 (5H, m), 2.73-2.98 (6H, m), 2.88 (3H, s), 3.23 (3H,
s), 3.77 (3H, s), 4.31 (1H, m), 6.82 (4H, s), 6.89 (2H, d, J=8.3
Hz), 7.01 (2H, d, J=8.3 Hz), 7.63 (1H, t, J=7.8 Hz), 7.64 (1H, t,
J=7.8 Hz), 8.02 (1H, d, J=5.9 Hz), 8.13 (1H, d, J=8.3 Hz), 8.19
(1H, d, J=8.3 Hz), 8.23 (1H, d, J=7.3 Hz), 8.34 (1H, d, J=6.3 Hz),
8.40-8.47 (2H, m), 8.60 (1H, d, J=5.9 Hz), 9.28 (1H, s), 9.29 (1H,
s).
EXAMPLE 132
N-{1-[P-(4-Picolyloxy)Benzyl]-2-[4-(2-Pyrimidyl)Piperazinyl]Ethyl}-N-Methyl
-5-Isoquinolinesulfonamide
100 mg of the amorphous compound obtained in Example 42 was
dissolved in 10 ml of a mixture of dried tetrahydrofuran/dried
dimethylformamide (1:1), to the solution were added 34.8 mg of
4-picolyl chloride hydrochloride and then 24 mg of triethylamine,
and the mixture was stirred at a room temperature for 30 minutes.
After adding 10 mg of 60% sodium hydride, the mixture was stirred
overnight at a room temperature, and after adding 20 g of water,
extracted twice with 20 ml of chloroform. The extract was washed
with a saturated sodium chloride aqueous solution, dried over
magnesium sulfate, and evaporated to remove the solvent under a
reduced pressure. The resulting residue was applied to a silica gel
column and extracted with chloroform/methanol (100:1) to obtain 73
mg of the title compound in colorless amorphous form.
NMR (CDCl.sub.3) .delta. ppm: 2.45 (4H, complex), 2.5-2.75 (2H,
complex), 2.95 (3H, s), 3.65 (4H, complex), 4.22 (1H, complex), 5.0
(2H, s), 6.49 (1H, t, J=4.26 Hz), 6.6 (2H, d, J=8.0 Hz), 6.9 (2H,
d, J=8.0 Hz), 7.4 (2H, brd), 7.6 (1H, t, J=8.3 Hz), 8.11 (1H, d,
J=8.3 Hz), 8.23 (1H, d, J=6.64 Hz), 8.3 (2H, d, J=4.26 Hz), 8.37
(1H, dd, J=1.0, 6.6 Hz), 8.57 (1H, d, J=6.6 Hz), 8.65 (2H, brd),
9.25 (1H, d, J=1.0 Hz).
EXAMPLE 133
N-{1-[P-(2-Picolyloxy)Benzyl]-2-[4-(2-Pyrimidyl)Piperazinyl]Ethyl}-N-Methyl
-5-Isoquinolinesulfonamide
The same procedure as described in Example 132 was repeated except
that the same amount of 2-picolyl chloride hydrochloride was used
in place of 4-picolyl chloride hydrochloride, to obtain 74.4 mg of
the title compound in colorless amorphous form.
NMR (CDCl.sub.3) .delta. ppm: 2.45 (4H, complex), 2.5-2.9 (2H,
complex), 2.98 (3H, s), 3.75 (4H, complex), 4.2 (1H, complex), 5.13
(2H, s), 6.46 (1H, t, J=4.8 Hz), 6.65 (2H, d, J=8.0 Hz), 6.9 (2H,
d, J=8.0 Hz), 7.15 (1H, complex), 7.58 (2H, t, J=6.9 Hz), 7.75 (1H,
complex), 8.1 (1H, d, J=8.0 Hz), 8.2-8.35 (2H, complex), 8.3 (1H,
d, J=4.8 Hz), 8.58 (1H, d, J=6.6 Hz), 8.6 (1H, brs), 9.25 (1H,
s).
EXAMPLE 134
N-{1-P-(4-Picolyloxy)Benzyl]-2-[4-(2-Pyridyl)Piperazinyl]Ethyl}-N-Methyl-5-
Isoquinolinesulfonamide
The same procedure as described in Example 132 was repeated except
that the product of Example 46 was used in place of the amorphous
compound obtained in Example 42, to obtain the title compound in a
colorless amorphous form in a yield of 53.5%.
NMR (CDCl.sub.3) .delta. ppm: 2.5 (4H, complex), 2.5-2.75 (2H,
complex), 2.95 (3H, s), 3.38 (4H, complex), 4.22 (1H, complex), 5.0
(2H, s), 6.58 (2H, d, J=8.6 Hz), 6.6 (2H, t, J=5.7 Hz), 6.9 (2H, d,
J=8.6 Hz), 7.35-7.5 (4H, complex), 7.58 (1H, t, J=7.8 Hz), 8.07
(1H, d, J=8.1 Hz), 8.17 (1H, brd), 8.23 (1H, d, J=6.1 Hz), 8.35
(1H, dd, J=1.0, 7.4 Hz), 8.57 (1H, d, J=6.1 Hz), 8.63 (1H, brd),
8.63 (1H, d, J=5.8 Hz), 9.2 (1H, d, J=1.0 Hz).
EXAMPLE 135
N-{ 1-(P-(2-Picolyloxy)Benzyl]-2-[4-(
2-Pyridyl)Piperazinyl]Ethyl}-N-Methyl-5-Isoquinolinesulfonamide
The same procedure as described in Example 133 was repeated except
that the product of Example 46 was used in place of the amorphous
compound obtained in Example 42, to obtain the title compound in a
colorless amorphous for in a yield of 59.5%.
NMR (CDCl.sub.3) .delta. ppm: 2.5 (4H, complex), 2.5-2.9 (2H,
complex), 2.95 (3H, s), 3.38 (4H, complex), 4.22 (1H, complex),
5.12 (2H, s), 6.55-6.65 (2H, complex), 6.54 (2H, d, J=8.6 Hz), 6.9
(2H, d, J=8.6 Hz), 7.2-7.25 (1H, complex), 7.4-7.7 (4H, complex),
7.65-7.8 (1H, complex), 8.1 (1H, d, J=7.7 Hz), 8.2 (1H, brd), 8.27
(1H, d, J=6.6 Hz), 8.3 (1H, d, J=6.6 Hz), 8.57 (1H, d, J=6.3 Hz),
8.6 (1H, brs), 9.73 (1H, s).
EXAMPLE 136
N-(2-Aminoethyl)-N-[2-(4-Benzyloxycarbonylpiperazinyl)-1-(P-Methoxybenzyl)E
thyl]-5-Isoquinolinesulfonamide
1.0 g of the product obtained in Example 73 was dissolved in 5 ml
of tetrahydrofuran, to the solution were added 685 mg of
triphenylphosphine and 340 mg of N-tert-butoxycarbonylethanolamine,
and then added dropwise a solution of 530 mg of diisopropyl
azodicarboxylate in 3 ml of tetrahydrofuran with stirring in a ice
bath. After removing from the ice bath, the mixture was stirred at
a room temperature for 3 hours and poured to water, and the mixture
was alkalized with sodium bicarbonate and extracted twice with 150
ml of chloroform. The extract was dried over magnesium sulfate and
the solvent was evaporated off under a reduced pressure. Resulting
oil was dissolved in 2 ml of ethyl acetate, to the solution was
added 30 ml of 4N hydrochloric acid in ethyl acetate, and the
mixture was stirred at a room temperature for 30 minutes. After
adding 100 ml of 1N hydrochloric acid, the reaction mixture was
washed twice with ethyl acetate, and the aqueous layer was
alkalized with sodium Obicarbonate and extracted twice with 150 ml
of chloroform. The extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure, and
resulting oil was applied to a silica gel column and eluted with
chloroform/methanol (100:1 to 50:1) to obtain 400 mg of the title
compound in colorless amorphous form.
IR (KBr) cm.sup.-1 : 1701, 1514, 1325, 1248, 1135, 763, 601;
NMR (CDCl.sub.3) .delta. ppm: 1.99 (2H, brs), 2.15-2.40 (5H, m),
2.55-2.80 (3H, m), 2.90-3.10 (2H, m), 3.20-3.70 (6H, m), 3.73 (3H,
s), 4.98 (1H, m), 5.10 (2H, s), 6.54 (2H, d, J=8.55 Hz), 6.77 (2H,
d, J=8.55 Hz), 7.33 (5H, s), 7.62 (1H, dd, J=8.06, 7.57 Hz), 8.14
(1H, d, J=8.06 Hz), 8.34 (1H, d, J=6.10 Hz), 8.39 (1H, d, J=7.57
Hz), 8.63 (1H, d, J=6.10 Hz), 9.28 (1H, s).
EXAMPLE 137
N-[2-(4-Benzyloxycarbonylpiperazinyl-1-P-Methoxybenzyl)Ethyl]-N-(2-Dimethyl
aminoethyl)- 5-Isoquinolinesulfonamide
6.08 g of the product obtained in Example 73 was dissolved in 30 ml
of tetrahydrofuran, to the solution were added 5.0 g of
triphenylphosphine and 1.42 g of N,N-dimethylethanolamine, and then
added dropwise a solution of 3.21 g of diisopropyl azodicarboxylate
in 10 ml of tetrahydrofuran with stirring in ice bath. After
removing from the ice bath, the reaction mixture was stirred at a
room temperature for 3 hours, diluted with ethyl acetate, and
extracted with 100 ml of 1N hydrochloric acid. The extract was
alkalized with sodium bicarbonate and extracted twice with 100 ml
of chloroform, and the extract was dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure.
Resulting oil was applied to a silica gel column and eluted with
chloroform/methanol (200:1 to 100:1), to obtain 4.99 g of the title
compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1703, 1514, 1327, 1247, 1135, 600;
NMR (CDCl.sub.3) .delta. ppm: 2.10-2.45 (5H, m), 2.26 (6H, s),
2.45-2.85 (5H, m), 3.20-3.65 (6H, m), 3.73 (3H, s), 4.00 (1H, m),
5.10 (2H, s), 6.53 (2H, d, J=8.79 Hz), 6.83 (2H, d, J=8.79 Hz),
7.34 (5H, s), 7.56 (1H, dd, J=8.05, 7.57 Hz), 8.10 (1H, d, J=8.05
Hz), 8.31 (1H, d, J=6.10 Hz), 8.35 (1H, d, J=7.57 Hz), 8.59 (1H, d,
J=6.10 Hz), 9.25 (1H, s).
EXAMPLE 138
N-(2-Acetoxyethyl)-N-[2-(4-Benzyloxycarbonylpiperazinyl)-1-(P-Methoxybenzyl
)Ethyl]-5-Isoquinolinesulfonamide
1.0 g of the product obtained in Example 73 was dissolved in 5 ml
of tetrahydrofuran, to the solution were added 220 mg of ethylene
glycol monoacetate and 85 mg of triphenylphosphine in place of
N-tert-butoxycarbonylethanolamine, according to the procedure
described in Example 136, to obtain 600 mg of the title compound in
a colorless amorphous form.
NMR (CDCl.sub.3) .delta. ppm: 2.04 (3H, s), 2.20-2.45 (5H, m),
2.60-2.80 (3H, m), 3.20-3.40 (4H, m), 3.45-3.73 (2H, m), 3.74 (3H,
s), 4.04 (1H, m), 4.27 (2H, t, J=6.84 Hz), 5.10 (2H, s), 6.54 (2H,
d, J=8.55 Hz), 6.82 (2H, d, J=8.55 Hz), 7.34 (5H, s), 7.59 (1H, dd,
J=8.05, 7.57 Hz), 8.13 (1H, d, J=8.05 Hz), 8.30 (1H, d, J=6.10 Hz),
8.36 (1H, d, J=7.57 Hz), 9.27 (1H, s).
EXAMPLE 139
N-[2-(4-Benzyloxycarbonylpiperazinyl)-1-(P-Methoxybenzyl)Ethyl]-N-(2-Hydrox
yethyl)-5-Isoquinolinesulfonamide
600 mg of the amorphous compound obtained in Example 138 was
dissolved in 6 ml of methanol and 3 ml of tetrahydrofuran, to the
solution was added 6 ml of 1N sodium hydroxide aqueous solution,
and the mixture was stirred at a room temperature for 2 hours. The
reaction mixture was diluted with water and extracted twice with 50
ml of chloroform, and the extract was washed with saturated sodium
chloride aqueous solution, dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure.
Resulting oil was applied to a silica gel column and eluted with
chloroform/methanol (100:1 to 50:1) to obtain 403 mg of the title
compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1701, 1514, 1433, 1332, 1249, 1136;
NMR (CDCl.sub.3) .delta. ppm: 2.10-2.25 (3H, m), 2.25-2.50 (4H, m),
2.50-2.70 (1H, m), 3.10-3.45 (5H, m), 3.55-3.75 (2H, m), 3.76 (3H,
s), 4.00-4.20 (2H, m), 5.08 (2H, s), about 5.4 (1H, br), 6.70 (2H,
d, J=8.79 Hz), 6.79 (2H, d, J=8.79 Hz), 7.32 (5H, s), 7.73 (1H, dd,
J=8.30, 7.32 Hz), 8.22 (1H, d, J=8.3 Hz), 8.50 (1H, d, J=7.32 Hz),
8.63 (1H, d, J=6.10 Hz), 8.72 (1H, d, J=6.10 Hz), 9.34 (1H, s).
EXAMPLE 140
N-{2-[4-(3,4-Dichlorobenzylamino)Piperidino]-1-(P-Methoxybenzyl)Ethyl}-N-Me
thyl-5-Isoquinolinesulfonamide
The amorphous compound obtained in Example 94 was subjected to
alkaline hydrolysis, methylation with methyl iodide and potassium
carbonate in dimethylformamide/tetrahydrofuran (1:1), and reflux
with 3N hydrochloric acid, to obtain
N-{1-(p-methoxybenzyl)-2-(4-oxopiperidino)ethyl}-N-methyl-5-isoquinolinesu
lfonamide in a colorless amorphous form.
NMR (CDCl.sub.3) .delta. ppm: 2.37 (4H, t, J=5.99 Hz), 2.40-2.90
(8H, m), 2.94 (3H, s), 3.74 (3H, s), 4.23 (1H, m), 6.51 (2H, d,
J=8.55 Hz), 6.83 (2H, d, J=8.55 Hz), 7.55 (1H, dd, J=8.32, 7.50
Hz), 8.10 (1H, d, J=8.32 Hz), 8.19 (1H, d, J=7.50 Hz), 8.19 (1H, d,
J=6.10 Hz), 8.55 (1H, d, J=6.10 Hz), 9.25 (1H, s).
3.34 g of this compound was dissolved in 30 ml of methanol, to the
solution were added 1.89 g of 3,4-dichlorobenzylamine and 0.6 ml of
acetic acid, and the mixture was stirred at a room temperature for
3 hours. The reaction mixture was cooled in a ice bath, and after
adding 450 mg of sodium cyanoborohydride, stirred with ice cooling
for 30 minutes and then at a room temperature for one hour. This
reaction mixture was alkalized with sodium bicarbonate and
extracted twice with 150 ml of chloroform, and the extract was
dried over magnesium sulfate and evaporated to remove the solvent
under a reduced pressure. Resulting oil was applied to a silica gel
column and eluted with chloroform/methanol (100:1 to 50:1), to
obtain 2.78 g of the title compound in a colorless amorphous
form.
IR (KBr) cm.sup.-1 : 1514, 1327, 1249, 1157, 1130, 826, 600;
NMR (CDCl.sub.3) .delta. ppm: 1.05-1.40 (2H, m), 1.60-2.15 (4H, m),
2.30-2.90 (8H, m), 2.93 (3H, s), 3.73 (5H, s), 4.13 (1H, m), 6.49
(2H, d, J=8.79 Hz), 6.83 (2H, d, J=8.79 Hz), 7.15 (1H, dd, J=8.20,
1.95 Hz), 7.38 (1H, d, J=8.20 Hz), 7.44 (1H, d, J=1.95 Hz), 7.56
(1H, dd, J=8.06, 7.57 Hz), 8.08 (1H, d, J=8.06 Hz), 8.19 (1H, d,
J=6.35 Hz), 8.29 (1H, d, J=7.57 Hz), 8.55 (1H, d, J=6.35 Hz), 9.23
(1H, s).
EXAMPLE 141
N-[2-{4-[N-(3,4-Dichlorobenzyl)-N-Methylamino]Piperidino}-1
-(P-Methoxybenzyl)Ethyl]]-N-Methyl-5-Isoquinolinesulfonamide
1.62 g of the amorphous compound obtained in Example 140 was
dissolved in 10 ml of tetrahydrofuran and 10 ml of
dimethylformamide, to the solution was added 115 mg of 60% sodium
hydride with stirring under ice cooling, and the mixture was
allowed to react at the same temperature for 5 minutes and then at
a room temperature for 15 minutes and again ice-cooled. After
adding 405 mg of methyl iodide, the mixture was allowed to react at
the same temperature for 5 minutes and then at a room temperature
for 2 hours, and poured to water. The mixture was extracted with
200 ml of ethyl acetate, and the extract was washed with a
saturated sodium chloride aqueous solution, dried over magnesium
sulfate and evaporated to remove the solvent under a reduced
pressure. Resulting oil was applied to a silica gel column and
eluted with chloroform/methanol (200:1 to 100:1) to obtain 880 mg
of the title compound in a colorless amorphous form.
IR (KBr) cm.sup.-1 : 1514, 1329, 1249, 1157, 1131, 826, 600;
NMR (CDCl.sub.3) .delta. ppm: 1.10-2.10 (6H, m), 2.14 (3H, s),
2.20-3.00 (7H, m), 2.93 (3H, s), 3.46 (2H, s), 3.73 (3H, s), 4.12
(1H, m),6.51 (2H, d, J=8.55 Hz), 6.85 (2H, d, J=8.55 Hz), 7.15 (1H,
dd, J=8.30, 1.71 Hz), 7.37 (1H, d, J=8.30 Hz), 7.42 (1H, d, J=1.71
Hz), 7.56 (1H, t, J=7.82 Hz), 8.08 (1H, d, J=7.82 Hz), 8.20 (1H, d,
J=6.11 Hz), 8.30 (1H, d, J=7.82 Hz), 8.56 (1H, d, J=6.11 Hz), 9.23
(1H, s).
REFERENCE EXAMPLE 39
4-Chlorocinnamyl Alcohol
25.9 g of p-chlorocinnamic acid was dissolved in 250 ml of
methanol, to the solution was added 1.5 ml of concentrated sulfuric
acid, and the mixture was refluxed for 2 hours. The reaction
mixture was poured on ice, and the mixture was alkalized with
sodium bicarbonate and extracted twice with 1000 ml of chloroform.
The extract was washed with a saturated sodium chloride aqueous
solution, dried over magnesium sulfate and evaporated to remove the
solvent under a reduced pressure, and resulting residue was applied
to a silica gel column and eluted with hexane/ethyl acetate (10:1),
to obtain 26.5 g of the methyl p-chlorocinnamate.
This compound was dissolved in 250 ml of toluene, to the solution
was added 200 ml of 1.5M diisobutyl aluminum hydride in toluene
with stirring under ice cooling, and the mixture was stirred for 2
hours. The reaction mixture was poured on ice, acidified with
concentrated hydrochloric acid, and extracted twice with 700 ml of
benzene. The extract was washed with a saturated sodium chloride
aqueous solution, dried over magnesium sulfate and evaporated to
remove the solvent under a reduced pressure, and resulting residue
was applied to a silica gel column and eluted with hexane/ethyl
acetate (4:1), to obtain 21.0 g of the title compound as colorless
crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 4.33 (2H, brs), 6.33 (1H,
dt, J=17.1, 5.7 Hz), 6.59 (1H, dt, J=17.1, 2.0 Hz), 7.29 (4H,
s).
REFERENCE EXAMPLE 40
N-4-Chlorocinnamyl-1,2-Phenylenediamine
11.9 g of the crystals obtained in Reference Example 39 was
dissolved in 120 ml of chloroform, to the solution was added 10.1 g
of thionyl chloride with stirring in an ice bath, and after
removing from the ice bath, the mixture was stirred for one hour
while allowing the reaction temperature to rise up to a room
temperature. Chloroform and excess thionyl chloride were evaporated
off under a reduced pressure, to the residue was added benzene, and
the solvent was evaporated off under a reduced pressure. Resulting
residue was applied to a silica gel column ano eluted with
hexane/ethyl acetate (15:1), to obtain 11.3 g of 4-chlorocinnamyl
chloride as colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 4.23 (2H, dd, J=6.3, 1.0
Hz), 6.29 (1H, dt, J=16.6, 6.9 Hz), 6.62 (1H, dt, J=16.6, 1.0 Hz),
7.30 (4H, s).
19.6 g of 1,2-phenylenediamine was dissolved in 300 ml of
dimethylformamide, to the solution were added 11.3 g of the
above-prepared 4-chlorocinnamyl chloride crystals and 12.5 g of
potassium carbonate at a room temperature with stirring, and the
mixture was stirred for 48 hours under the same condition. After
adding water and sodium chloride, the reaction mixture was
extracted twice with 1000 ml of chloroform, and the extract was
dried over magnesium sulfate and evaporated to remove the solvent
under a reduced pressure. Resulting residue was applied to a silica
gel column and eluted with hexane/ethyl acetate (3:1), to obtain
12.85 g of the title compound as colorless crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 3.4 (3H, brs), 3.93 (2H,
dd, J=5.71, 1.0 Hz), 6.36 (1H, dt, J=16.0, 5.71 Hz), 6.59 (1H, dt,
J=16.0, 1.0 Hz), 6.68-6.9 (4H, m), 7.28 (4H, s).
EXAMPLE 142
N-[2-(4-Chlorocinnamylamino)Phenyl]-5-Isoquinolinesulfonamide
12.85 g of the crystals obtained in Reference Example 40 was
dissolved in 200 ml of pyridine, to the solution was added 15.1 g
of 5-isoquinolinesulfonyl chloride, hydrochloride with stirring in
a ice bath, and after removing from the ice bath, the mixture was
allowed to react at a room temperature for 18 hours. The reaction
mixture was poured on ice, alkalized with sodium bicarbonate and
extracted twice with 1000 ml of chloroform. The extract was dried
over magnesium sulfate and the solvent was evaporated off under a
reduced pressure to form scarcely soluble crystals. To the crystals
was added chloroform, the whole was refluxed and then cooled, and
the resulting crystals was collected by suction filtration, washed
with chloroform and dried under a reduced pressure, to obtain 17.23
g of the title compound as colorless crystals.
Melting point: 205.degree.-208.degree. C. (decomposed);
IR (KBr) cm.sup.-1 : 1600, 1320, 1150, 1135;
.sup.1 H-NMR (CDCl.sub.3 +CD.sub.3 OD, .delta. ppm): 3.73 (2H, dd,
J=5.62, 1.46 Hz), 6.04 (1H, dt, J=15.8, 5.37 Hz), 6.27-6.35 (2H,
m), 6.42 (1H, dt, J=16.11, 1.46 Hz), 6.58 (1H, d, J=7.81 Hz), 7.04
(1H, ddd, J=8.30, 6.10, 2.93 Hz), 7.25 (2H, d, J=9.03 Hz), 7.31
(2H, d, J=9.03 Hz), 7.63 (1H, dd, J=8.06, 7.33 Hz), 8.17 (1H, dd,
J=7.32 , 0.98 Hz), 8.30 (1H, dd, J=7.57, 1.23 Hz), 8.47 (1H, dd,
J=6.35, 1.02 Hz), 8.55 (1H, d, J=6.35 Hz), 9.25 (1H, d, J=0.98
Hz).
EXAMPLE 143
N-[2-(4-Chlorocinnamylamino)Phenyl]-N-Methyl-5
-Isoquinolinesulfonamide
380 mg of the crystals obtained in Example 142 was dissolved in 6
ml of methanol, to the solution was added 10 ml of a solution of
diazomethane in ether at a room temperature with stirring, and the
mixture was stirred for 18 hours. The solvent was evaporated off
under a reduced pressure to obtain an oil, which was then applied
to a silica gel column and eluted with hexane/ethyl acetate (1:1)
to obtain acetate, which was then recrystallized from hexane/ethyl
acetate to obtain 270 mg of the title compound as colorless
crystals.
Melting point: 149.degree.-151.degree. C.;
IR (KBr) cm.sup.-1 : 1595, 1325, 1125, 830, 745;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 3.24 (3H, s), 3.87 (2H, m),
4.81 (1H, t, J=5.71 Hz), 6.13 (1H, dt, J=19.14, 5.71 Hz), 6.25-6.40
(2H, m), 6.53 (1H, dt, J=19.14, 1.0 Hz), 6.67 (1H, d, J=8.57 Hz),
7.05-7.18 (1H, m), 7.28 (4H, s), 7.67 (1H, t, J=7.42 Hz), 8.19 (1H,
d, J=7.42 Hz), 8.28 (1H, d, J=6.28 Hz), 8.32 (1H, dd, J=7.42, 1.0
Hz), 8.51 (1H, d, J=6.28 Hz), 9.30 (1H, d, J=1.0 Hz).
EXAMPLE 144
1-(4-Chlorocinnamyl)-4-(5-Isoquinolinesulfonyl)-1,2,3,4-Tetrahydroquinoxali
ne
5.0 g of the crystals obtained in Example 142 was dissolved in 75
ml of dimethylformamide, to the solution was added 4.6 g of
potassium carbonate and 2.19 g of 1,2-dibromoethane at a room
temperature with stirring, and the mixture was stirred for 60
hours. The reaction mixture was poured in water, saturated with
sodium chloride, and extracted twice with 400 ml of chloroform. The
extract was dried over magnesium sulfate, evaporated to remove the
solvent undr a reduced prssure. Resulting residue was applied to a
silica gel column and eluted with chloroform/methanol (400:1) and
then hexane/ethyl acetate (2:1), to obtain 3.32 g of the title
compound in yellow amorphous form.
IR (KBr) cm.sup.-1 : 1600, 1340, 1150, 1130, 660;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.68 (2H, t, J=5.71 Hz),
3.49 (2H, dd, J=6.28, 1.0 Hz), 3.89 (2H, t, J=5.71 Hz), 5.43 (1H,
dt, J=15.42, 6.28 Hz), 6.10 (1H, dt, J=15.42, 1.0 Hz), 6.48 (1H,
dd, J=7.99, 1.0 Hz), 6.75 (1H, dt, J=7.99, 1.0 Hz), 7.09 (2H, d,
J=7.99 Hz), 7.12 (1H, dt, J=7.99, 1.0 Hz), 7.31 (2H, d, J=7.99 Hz),
7.54 (1H, dd, J=7.99, 1.0 Hz), 7.59 (1H, t, J=7.99 Hz), 7.77 (1H,
d, J=6.28 Hz), 7.94 (1H, d, J=7.99 Hz), 8.30 (1H, d, J=6.28 Hz),
8.38 (1H, dd, J=7.99, 1.0 Hz), 9.03 (1H, d, J=1.0 Hz).
EXAMPLE 145
The same procedure as described in Example 142 was repeated except
that N-[3-(3-pyridyl)allyl]-1,2-phenylenediamine was used in place
of N-(4-chlorocinnamyl)-1,2-phenylenediamine, to obtain
N-{2-[3-(3-pyridyl)allylamino]phenyl}-5-isoquinolinesulfonamide in
a brown amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.2 (1H, br), 3.78 (2H, dd,
J=5.14, 1.0 Hz), 4.85 (1H, br), 6.14 (1H, dt, J=15.99, 5.14 Hz),
6.33 (2H, d, J=4.57 Hz), 6.42 (1H, dt, J=15.99, 1.0 Hz), 6.58 (1H,
d, J=7.42 Hz), 6.98-7.15 (1H, m), 7.26 (1H, dd, J=7.42, 4.57 Hz),
7.59 (1H, t, J=7.42 Hz), 7.65 (1H, dt, J=7.42, 1.0 Hz), 8.16 (1H,
d, J=7.99 Hz), 8.30 (1H, d, J=6.85 Hz), 8.35-8.53 (3H, m), 8.56
(1H, d, J=6.28 Hz), 9.32 (1H, s).
EXAMPLE 146
The amorphous compound obtained in Example 145 was treated
according to the procedure in Example 143 to obtain
N-{2-[3-(3-pyridyl)allylamino)phenyl}-N-methyl-5-isoquinolinesulfonamide.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 3.24 (3H, s), 3.92 (2H, t,
J=4.57 Hz), 4.90 (1H, t, J=5.71 Hz), 6.26 (1H, dt, J=15.42, 5.14
Hz), 6.32 (2H, d, J=4.57 Hz), 6.58 (1H, dt, J=15.42, 1.0 Hz),
6.62-6.74 (2H, m), 7.05-7.20 (1H, m), 7.26 (1H, dd, J=7.99, 4.57
Hz), 7.6-7.75 (1H, m), 8.21 (1H, d, J=7.99 Hz), 8.28 (1H, d, J=6.85
Hz), 8.32 (1H, d, J=6.28 Hz), 8.47 (1H, dd, J=5.71, 1.0 Hz), 8.51
(1H, d, J=6.28 Hz), 8.58 (1H, d, J=1.7 Hz), 9.31 (1H, s).
REFERENCE EXAMPLE 41
2-Amino-3-(4-Chlorocinnamylamino)Pyridine
7.71 g of p-chlorocinnamyl chloride and 13.5 g of
2,3-diaminopyridine were dissolved in 220 ml of dimethylformamide,
and to the solution was added 8.6 g of potassium carbonate, and the
mixture was stirred at a room temperature for 50 hours, and after
adding 300 ml of water, extracted twice with 200 ml of chloroform.
The extract was dried over magnesium sulfate and concentrated under
a reduced pressure, and resulting residue was applied to a silica
gel column and eluted with chloroform/methanol (100:1 to 50:1), to
obtain 4.52 g of the title compound as yellow crystals.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 3.38 (1H, br), 3.92 (2H,
m), 4.20 (2H, br), 6.31 (1H, dt, J=16.1, 5.9 Hz), 6.59 (1H, dt,
J=16.1, 1.5 Hz), 6.71 (1H, dd, J=4.9, 7.8 Hz), 6.86 (1H, dd, J=1.5,
7.8 Hz), 7.29 (4H, s), 7.63 (1H, dd, J=1.5, 4.9 Hz).
EXAMPLE 147
3-(4-Chlorocinnamylamino)-2-(5-Isoquinolinesulfonylamino)Pyridine
4.52 g of the crystals obtained in Reference Example 41 was
dissolved in 50 ml of pyridine, to the solution were added 5.8 g of
5-isoquinolinesulfonyl chloride hydrochloride and 3 g of
dimethylaminopyridine, and the mixture was stirred for 18 hours at
a room temperature, after adding 150 ml of water, extracted twice
with 80 ml of chloroform. The extract was dried over magnesium
sulfate and concentrated under a reduced pressure, and resulting
residue was applied to a silica gel column and eluted with
chloroform/methanol (100:1), and resulting crystals was washed with
ethyl acetate, to obtain 1.2 g of the title compound as yellow
crystals.
Melting point: 211.degree.-217.degree. C. (decomposed);
IR (KBr) cm.sup.-1 : 1595, 1550, 1345, 1285, 1250, 1105;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 3.89 (2H, m), 5.45 (1H, t,
J=5.9 Hz), 6.12 (1H, dt, J=16.1, 5.4 Hz), 6.45 (1H, d, J=16.1 Hz),
6.51-6.62 (2H, m), 6.92 (1H, brs), 7.21 (2H, d, J=8.8 Hz), 7.29
(2H, d, J=8.8 Hz), 7.64 (1H, dd, J=7.3, 8.3 Hz), 8.12 (1H, d, J=8.3
Hz), 8.45 (1H, dd, J=1.0, 7.3 Hz), 8.64 (1H, d, J=5.9Hz), 8.69 (1H,
d, J=5.9 Hz), 9.31 (1H, s).
REFERENCE EXAMPLE 42
Methyl 4-Amino-3-(4-Chlorocinnamylamino)Benzoate
5.0 g of methyl 3,4-diaminobenzoate was dissolved in 40 ml of
dimethylformamide, and to the solution were added 2.07 g of
potassium carbonate and 1.87 g of p-chlorocinnamyl chloride, and
reaction was carried out according to the procedure in Reference
Example 40, to obtain 2.0 g of the title compound as a light brown
oil.
NMR (CDCl.sub.3) .delta. ppm: 3.85 (3H, s), 3.94 (2H, brd), 6.35
(1H, dt, J=5.86, 15.8 Hz), 6.59 (1H, d, J=5.8 Hz), 6.7 (1H, d,
J=8.02 Hz), 7.28 (4H, s), 7.4 (1H, d, J=1.4 Hz), 7.46 (1H, dd,
J=1.4, 8.0 Hz).
EXAMPLE 148
Methyl
4-(5-Isoquinolinesulfonamino)-3-(4-Chlorocinnamylamino)Benzoate
1.8 g of the oil obtained in Reference Example 42 was dissolved in
18 ml of pyridine, to the solution was added 1.29 g of
5-isoquinolinesulfonyl chloride hydrochloride with stirring under
ice cooling, and the mixture was treated according to the procedure
in
EXAMPLE 142 to obtain residue, which was then applied to a silica
gel column and eluted with chloroform/methanol (100:1), to obtain
1.28 g of the title compound as light yellow crystals.
Melting point: 143.degree.-145.degree. C. (subliming at a higher
temperature than melting point);
NMR (CDCl.sub.3) .delta. ppm: 3.78 (2H, brd), 3.82 (3H, s), 6.0
(1H, dt, J=5.86, 15.87 Hz), 6.4 (1H, d, J=15.8 Hz), 6.45 (1H, d,
J=8.3 Hz), 7.05 (lH dd, J=1.8, 8.3 Hz), 7.2-7.3 (5H, brs), 7.60
(1H, t, J=7.6 Hz), 8.15 (1H, d, J=8.3 Hz), 8.29 (1H, dd, J=1.2, 7.3
Hz), 8.43 (1H, d, J=6.1 Hz), 8.61 (1H, d, J=6.1 Hz), 9.3 (1H, d,
J=1.2 Hz).
REFERENCE EXAMPLE 43
N-Cinnamyl-1,2-Phenylenediamine
3.24 g of ortho-phenylenediamine was dissolved in 30 ml of
dimithylformaide, to the solution were added 2.07 g of potassium
carbonate and 1.52 g of cinnamyl chloride, and the mixture was
stirred overnight at a room temperature. After adding 100 ml of
water, the reaction mixture was extracted twice with 100 ml and 50
ml of chloroform, and the extract was washed with a saturated
sodium chloride aqueous solution, dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure The
resulting residue was applied to a silica gel column and eluted
with chloroform, to obtain 2.0 g of the title compound as light
brown crystals.
Melting point 59.degree.-66.degree. C. (decomposed);
NMR (CDCl.sub.3) .delta. ppm: 3.3 (2H, brs), 3.93 (2H, brd), 6.4
(1H, d and t, J=5.6, 16.1 Hz), 6.1-6.45 (4H, complex) 5.2-5.7 (5H,
complex).
EXAMPLE 149
N-(2-Cinnamylamino)phenyl-5-Isoquinolinesulfonamide
1.8 g of the crystals obtained in Reference Example 43 was
dissolved in 18 ml of pyridine, to the solution was added 1.83 g of
isoquinolinesulfonyl chloride hydrochloride, and the mixture was
stirred for 18 hours at a room temperature. After adding 50 ml of
water, the reaction mixture was extracted twice with ml of
chloroform, and the extract was washed with a saturated sodium
chloride aqueous solution, dried over magnesium sulfate and
evaporated to remove the solvent under a reduced pressure. The
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1), to obtain 2.40 g of the title
compound as pale reddish crystals.
Melting point: 181.degree.-185.degree. C.;
NMR (CDCl.sub.3) .delta. ppm: 3.75 (2H, brd), 4.55 (1H, brs), 6.05
(1H, d and t, J=5.6, 16.1 Hz), 6.35 (2H, brd), 6.45 (1H, d, J=16.1
Hz) 6.63 (1H, d, J=8.3 Hz), 7-7.13 (1H, complex), 7.25-7.4 (5H,
complex), 7.6 (1H, t, J=8.2 Hz), 8.15 (1H, d, J=8.3 Hz), 8.31 (1H,
dd, J=1.0, 8.2 Hz), 8.4 (1H, d, J=6.6 Hz), 8.65 (1H, d, J=6.6 Hz),
9.3 (1H, d, J=1.0 Hz).
REFERENCE EXAMPLE 44
N-(4-Chlorocinnamyl)-1,3-Phenylenediamine
3.24 g of metha-phenylenediamine was dissolved in 40 ml of
dimethylformamide, to the solution were added 2.07 g of potassium
carbonate and 1.87 g of p-chlorocinnamyl chloride, and the mixture
was subjected to react according to the procedure in Reference
Example 40. The resulting residue was applied to a silica gel
column and eluted with n-hexane/ethyl acetate (3:1 to 2:1), to
obtain 1.70 g of the title compound as a light brown oil.
NMR (CDCl.sub.3) .delta. ppm: 3.65 (2H, brs), 3.90 (2H, dd, J=1.4,
5.6 Hz), 6.0-6.2 (3H, complex), 6.3 (1H, dd, J=5.6, 15.9 Hz), 6.56
(1H, dd, J=1.4, 15.9 Hz), 6.97 (1H, t, J=8.1 Hz), 7.3 (4H, s).
EXAMPLE 150
N-[3-(4-Chlorocinnamylamino)Phenyl]-5-Isoquinolinesulfonamide
1.7 g of the oil obtained in Reference Example 44 was dissolved in
18 ml of pyridine, to the solution was added 1.99 g of
5-isoquinolinesulfonyl chloride.HCl with stirring under a ice
cooling, and the same procedure as described in Example 142 was
repeated to obtain 1.45 g of the title compound as a light brown
oil.
NMR (CDCl.sub.3).delta. ppm: 3.8 (2H, brd), 3.92 (1H, brs), 6.15
(1H, d and t, J=5.6, 15.9 Hz), 6.25 (1H, brs), 6.35 (2H, brd), 6.49
(1H, d, J=15.9 Hz), 6.92 (1H, t, J=8.1 Hz), 7.3 (4H, s), 7.51 (1H,
t, J=8.3 Hz), 8.1 (1H, d, J=8.3 Hz), 8.35 (1H, dd, J=1.0, 8.3 Hz),
8.45 (1H, d, J=6.1 Hz), 8.65 (1H, d, J=6.4 Hz), 9.3 (1H, d, J=1.0
Hz).
EXAMPLE 151
N-{2-(P-Chlorocinnamylamino)Phenyl}-N-(2-Hydroxyethyl)-5-Isoquinolinesulfon
amide
1.5 g of the crystals obtained in Example 142 was dissolved in 8 ml
of tetrahydrofuran, to the solution were added 1.32 g of
triphenylphosphine and 420 mg of ethylene glycol monoacetate, and
also added dropwise a solution of 1.01 g of diisopropyl
azodicarboxylate in 2 ml of tetrahydrofuran with stirring in a ice
bath. After being removed from the ice bath, the mixture was warmed
to a room temperature, stirred for 3 hours, diluted with ethyl
acetate and extracted twice with 70 ml of 2N hydrochloric acid. The
aqueous layer was alkalized with sodium bicarbonate and extracted
twice with 150 ml of chloroform, and the extract was dried over
magnesium sulfate and evaporated under a reduced pressure to remove
the solvent. Resulting oily residue was dissolved in 20 ml of
methanol and 20 ml of tetrahydrofuran, to the solution was added 20
ml of 1N sodium hydroxide aqueous solution, and the reaction was
carried out at a room temperature for 2 hours. The reaction mixture
was diluted with water and extracted twice with 100 ml and 50 ml
each of chloroform, and th extract was dried over magnesium
chloride and evaporated under a reduced pressure to remove the
solvent. The resulting oil was applied to a silica gel column and
eluted with chloroform/methanol (100:1 to 50:1), to obtain 1.59 g
of the title compound in a yellow amorphous form.
IR (KBr) cm.sup.-1 : 1603, 1516, 1491, 1342, 1161, 1139, 835, 758,
604, 509;
NMR (CDCl.sub.3) .delta. ppm: 3.09 (1H, m), 3.29 (1H, ddd, J=13.43,
4.64, 3.18 Hz), 3.47 (1H, m), 3.75 (1H, m), 3.85 (2H, m), 4.33 (1H,
ddd, J=13.43, 8.30, 4.15 Hz), 5.12 (1H, m), 6.16 (1H, dt, J=15.87,
5.62 Hz), 6.23 (1H, dd, J=8.06, 1.47 Hz), 6.40 (1H, td, J=7.33,
1.47 Hz), 6.55 (1H, d, J=16.11 Hz), 6.76 (1H, d, J=8.54 Hz), 7.15
(1H, t, J=8.30 Hz), 7.29 (4H, s), 7.63 (1H, t, J=8.30 Hz), 8.18
(1H, d, J=8.30 Hz), 8.28 (1H, d, J=8.30 Hz), 8.28 (1H, d, J=6.35
Hz), 8.52 (1H, d, J=6.3 Hz), 9.31 (1H, s).
EXAMPLE 152
N-{2-(P-Chlorocinnamylamino)phenyl}-N-(2-Dimethylaminoethyl)-5-Isoquinoline
sulfonamide
2.0 g of the crystals obtained in Example 142 was dissolved in 10
ml of tetrahydrofuran, to the solution were added 1.75 g of
triphenylphosphine and 520 mg of N,N-dimethyl ethanolamine, and
thereto added dropwise a solution of 1.3 g of diisopropyl
azodicarboxylate in 3 ml of being tetrahydrofuran with stirring in
ice bath. After being removed from the ice bath, the mixture was
warmed to a room temperature, stirred for 3 hours, and then diluted
with ethyl acetate, and extracted twice with 100 ml of 2N
hydrochloric acid. The extract was alkalized with a sodium
bicarbonate aqueous solution and extracted twice with 200 ml of
chloroform. The extract was dried over magnesium sulfate and
evaporated under a reduced pressure to remove the solvent, and a
resulting oil was applied to a silica gel column and eluted with
chloroform/methanol (100:1), to obtain 1.35 g of the title compound
in a yellow amorphous form.
IR (KBr) cm.sup.-1 : 1603, 1521, 1491, 1458, 1329, 1160, 1137, 834,
749, 601, 507;
NMR (CDCl.sub.3) .delta. ppm: 2.19 (6H, s), 2.15-2.55 (2H, m), 3.19
(1H, dt, J=12.69, 4.15 Hz), 3.56 (2H, m), 4.35 (1H, m), 5.78 (1H,
m), 5.89 (1H, dt, J=15.87, 5.37 Hz), 6.30-6.55 (3H, m), 6.64 (1H,
dd, J=7.81, 1.71 Hz), 7.09 (1H, td, J=7.81, 1.71 Hz), 7.23 (2H, d,
J=9.03 Hz), 7.30 (2H, d, J=9.03 Hz), 7.57 (1H, dd, J=8.30, 7.57
Hz), 8.11 (1H, d, J=8.30 Hz), 8.24 (1H, d, J=7.57 Hz), 8.40 (1H, d,
J=6.35 Hz), 8.53 (1H, d, J=6.35 Hz), 9.26 (1H, s).
EXAMPLES 153 to 171
In Example 153 to 171 the following general reaction was used.
##STR22##
EXAMPLE 153
(n=2, Aryl=4-Chlorophenyl)
N-[2-(4-Chloro-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamid
e
7.30 g of N-(2-aminoethyl)-5-isoquinolinesulfonamide was dissolved
in 150 ml of methanol, to the solution was added 6.30 g of
p-chlorobenzalacetone, and the mixture was stirred at a room
temperature for 36 hours. After addition of 1.32 g of sodium
tetrahydrideborate with ice-water cooling, the mixture was stirred
for 30 minutes. The reaction mixture was concentrated to half of
original volume under a reduced pressure, and after adding 300 ml
of ethyl acetate, washed three times with water. The aqueous layer
was extracted with 100 ml of ethyl acetate, and the extract was
washed with water as described above. The ethyl acetate layers were
combined, washed twice with a saturated sodium chloride aqueous
solution, dried over magnesium sulfate, filtered, and evaporated
under a reduced pressure to remove the solvent. The resulting
residue was purified using a silica gel column (silica gel: 200 g;
eluant: 5% methanol in chloroform), to obtain 6.78 g of the title
compound in a colorless amorphous form, while recovering the
residual starting material.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.06 (3H, d, J=6.6 Hz),
1.8-2.8 (2H, br), 2.57-2.64 (2H, m), 2.96 (2H, t, J=5.7 Hz), 3.06
(1H, dq, J=7.8, 6.6 Hz), 5.79 (1H, dd, J=15.8, 7.8 Hz), 6.24 (1H,
d, J=15.8 Hz), 7.19 (2H, dm, J=8.8 Hz), 7.25 (2H, dm, J=8.8 Hz),
7.67 (1H, dd, J=8.0, 7.6 Hz), 8.28 (1H, dt, J=8.0, 1.0 Hz),
8.42-8.46 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0
Hz).
EXAMPLE 154
(n=2, Aryl=Phenyl)
N-[2-(.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NHR (CDCl3, .delta. ppm): 2.0-3.0 (2H, br), 2.59-2.66 (2H,
m), 2.98 (2H, t, J=5.5 Hz), 3.09 (1H, dq, J=8.0, 6.6 Hz), 5.80 (1H,
dd, J=15.9, 8.0 Hz), 6.28 (1H, d, J=15.9 Hz), 7.28 (5H, brs), 7.66
(1H, dd, J=8.3, 7.3 Hz), 8.17 (1H, brd, J=8.3 Hz), 8.43 (1H, dd,
J=7.3, 1.2 Hz), 8.44 (1H, d, J=6.1 Hz), 8.68 (1H, d, J=6.1 Hz),
9.34 (1H, d, J=1.0 Hz).
EXAMPLE 155
(N=2, Aryl =2,4-Difluorophenyl)
N-[2-(2,4-Difluoro-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfon
amide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.06 (3H, d, J=6.4 Hz),
1.3-2.2 (2H, br), 2.57-2.67 (2H, m), 2.96 (2H, t, J=5.6 Hz), 3.04
(1H, dq, J=8.0, 6.4 Hz), 5.81 (1H, dd, J=16.1, 8.0 Hz), 6.35 (1H,
d, J=16.1 Hz), 6.79 (1H, d, J=8.3 Hz and 1H, ddd, J=17.6, 8.8, 2.0
Hz), 7.30 (1H, ddd, J=14.9, 8.3, 2.0 Hz), 7.69 (1H, dd, J=8.3, 7.3
Hz), 8.29 (1H, dt, J=8.3, 1.0 Hz), 8.42-8.47 (2H, m), 8.70 (1H, d,
J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 156
(N=2, Aryl=2,4-Dichlorophenyl) N-[2
-(2,4-Dichloro-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamid
e
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.07 (3H, d, J=6.6 Hz),
1.5-2.5 (2H, br), 2.58-2.65 (2H, m), 2.97 (2H, t, J=5.5 Hz), 3.09
(1H, dq, J=8.0, 6.6 Hz), 5.75 (1H, dd, J=15.8, 8.0 Hz), 6.58 (1H,
d, J=15.8 Hz), 7.18 (1H, dd, J=8.5, 2.0 Hz), 7.28 (1H, d, J=8.5
Hz), 7.35 (1H, d, J=2.0 Hz), 7.68 (1H, dd, J=8.0, 7.3 Hz), 8.18
(1H, td, J=8.0, 1.0 Hz), 8.42-8.47 (2H, m), 8.70 (1H, d, J=6.1 Hz),
9.34 (1H, d, J=1.0 Hz).
EXAMPLE 157
(N=2, Aryl=3-Chlorophenyl) N-[2-(
3-Chloro-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.06 (3H, d, J=6.6 Hz),
1.3-2.4 (2H, br), 2.56-2.63 (2H, m), 2.97 (2H, t, J, 5.6 Hz), 3.06
(1H, dq, J=7.8, 6.6 Hz), 5.80 (1H, dd, J= 15.9, 7.8 Hz), 6.22 (1H,
d, J=15.9 Hz), 7.10-7 26 (4H, m), 7.68 (1H, dd, J=8.1, 7.5 Hz),
8.18 (1H, dt, J=8.1, 1.0 Hz), 8.42-8.47 (2H, m), 8.70 (1H, d, J=6.1
Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 158
(N=2, Aryl=2-Nitrophenyl)
N-2-(.alpha.-Methyl-2-Nitrocinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Light yellow amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.08 (3H, d, J=6.4 Hz),
1.3-2.6 (2H, br), 2.61-2.67 (2H, m), 2.99 (2H, t, J =5.6 Hz), 3.09
(1H, dq, J=7.8, 6.4 Hz), 5.73 (1H, dd, J=15.6, 7.8 Hz), 6.73 (1H,
d, J=15.6 Hz), 7.36-7.56 (3H, m), 7.68 (1H, dd, J=8.3, 7.3 Hz),
7.92 (1H, dd, J=7.9, 1.2 Hz), 8.42-8.47 (2H, m), 8.67 (1H, d, J=6.1
Hz), 9.31 (1H, d, J=1.0 Hz).
EXAMPLE 159
(N=2, Aryl=4-Nitrophenyl)
N-2-(.alpha.-Methyl-4-Nitrocinnamylamino)Ethyl]-5-Isoquinolinesulfonylamid
e
Light yellow amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.10 (3H, d, J=6.6 Hz),
1.4-2.6 (2H, br), 2.60-2.67 (2H, m), 2.99 (2H, t, J=5.5 Hz), 3.14
(1H, dq, J=7.6, 6.6 Hz), 6.05 (1H, dd, J=15.9, 7.6 Hz), 6.38 (1H,
d, J=15.9 Hz), 7.40 (2H, m, J=8.8 Hz), 7.69 (1H, dd, J=8.3, 7.5
Hz), 8.14 (2H, dm, J=8.8 Hz), 8.23 (1H, brd, J=8.3 Hz), 8.43-8.48
(2H, m), 8.68 (1H, d, J=6.1 Hz), 9.36 (1H, d, J=1.0 Hz).
EXAMPLE 160
(N=2, Aryl=4-Methylphenyl)
N-[2-(.alpha.,4-Dimethylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.05 (3H, d, J=6.6 Hz),
2.0-2.5 (2H, br), 2.33 (3H, s), 2.56-2.64 (2H, m), 2.96 (2H, t,
J=5.9 Hz), 3.05 (1H, m), 5.73 (1H, dd, J=15.9, 7.8 Hz), 6.24 (1H,
d, J=15.9 Hz), 7.09 (2H, brd, J=8.3 Hz), 7.16 (2H, brd, J=8.3 Hz),
7.67 (1H, t, J=8.0 Hz), 8.17 (1H, brd, J=8.0 Hz), 8.43 (1H, d,
J=8.0 Hz), 8.44 (1H, d, J=6.1 Hz), 8.68 (1H, d, J=6.1 Hz), 9.34
(1H, d, J=1.0 Hz).
EXAMPLE 161
(N=2, Aryl=3,4-Ethylenedioxyphenyl)
N-[2-(.alpha.-Methyl-3,4-Methylenedioxycinnamylamino)Ethyl]-5-Isoquinoline
sulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.04 (3H, d, J=6.3 Hz),
2.56-2.63 (2 H, m), 2.95 (2H, t, J=5.6 Hz), 3.05 (1H, dq, J=8.0,
6.3 Hz), 5.60 (1H, dd, J=15.9, 8.0 Hz), 5.95 (2H, s), 6.18 (1H, d,
J=15.9 Hz), 6.70 (1H, dd, J=7.5, 1.5 Hz), 6.73 (1H, d, J=7.5 Hz),
6.79 (1H, d, J=1.5 Hz), 7.68 (1H, dd, J=8.1, 7.5 Hz), 8.19 (1H,
brd, J=8.1 Hz), 8.42-8.46 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.35
(1H, d, J=1.0 Hz).
EXAMPLE 162
(n=2, Aryl=2-Pyridyl) N-{2-[
1-Methyl-3-(2-Pyridyl)-2-Propenylamino]Ethyl}-5-Isoquinolinesulfonamide
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.07 (3H, d, J=6.6 Hz),
1.5-4.0 (2H, br), 2.62 (2H, dt, J=5.7, 5.7 Hz), 2.97 (2H, t, J=6.4
Hz), 3.06 (1H, dq, J=5.6, 6.6 Hz), 6.35 (1H, d, J=5.6 Hz), 6.37
(1H, s), 7.12 (1H, dddd, J=7.8, 5.0, 2.0, 1.0 Hz), 7.21 (1H, d,
J=7.8 Hz), 7.62 (1H, td, J=7.8, 2.0 Hz), 7.68 (1H, dd, J=8.0, 7.3
Hz), 8.18 (1H, brd, J=8.0 Hz), 8.44 (1H, d, J=7.3 Hz), 8.45 (1H, d,
J=7.3 Hz), 8.52 (1H, ddd, J=5.0, 2.0, 1.0 Hz), 8.67 (1H, d, J=6.1
Hz), 9.34 (1H, d, J=1.0 Hz).
EXAMPLE 163
(N=2, Aryl=4-Pyridyl)
N-{2-[1-Methyl-3-(4-Pyridyl)-2-Propenylamino]ethyl}-5-Isoquinolinesulfonyl
amide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.09 (3H, d, J=6.3 Hz),
1.2-1.9 (2H, br), 2.59-2.65 (2H, m), 2.98 (2H, t, J=6.0 Hz), 3.12
(1H, dq, J=7.3, 6.3 Hz), 6.06 (1H, dd, J=15.9, 7.3 Hz), 6.26 (1H,
d, J=15.9 Hz), 7.14 (2H, dd, J=6.1, 1.5 Hz), 7.69 (1H, dd, J=8.1,
7.5 Hz), 8.19 (1H, brd, J=8.1 Hz), 8.42-8.47 (2H, m), 8.51 (2H, dd,
J=6.1, 1.5 Hz), 8.68 (1H, d, J=6.3 Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 164
N=2, Aryl=2-Thienyl)
N-{2-[1-Methyl-3-(2-Thienyl)-2-Procenylamino]ethyl}-5-Isoquinolinesulfonami
de
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.05 (3H, d, J=6.6 Hz),
1.2-2.5 (2H, br), 2.56-2.64 (2H, m), 2.93-3.05 (3H, m), 5.65 (1H,
dd, J=15.6, 8.0 Hz), 6.41 (1H, d, J=15.6 Hz), 6.85 (1H, dd, J=3.7,
2.4 Hz), 6.94 (1H, dd, J=4.9, 3.7 Hz), 7.13 (1H, dd, J=4.9, 2.4
Hz), 7.68 (1H, dd, J=8.3, 7.5 Hz), 8.19 (1H, brd, J=8.3 Hz),
8.42-8.46 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0
Hz).
EXAMPLE 165
(N=2, Aryl=2-Furyl)
N-{2-[3-(2-Furyl)-1-Methyl-2-Propenylamino]Ethyl}-5-Isoquinolinesulfonamid
e
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.04 (3H, d, J=6.4 Hz),
1.3-1.5 (2H, br), 2.59 (2H, td, J=6.0, 4.9 Hz), 2.95 (2H, t, J=6.0
Hz), 2.98 (1H, dq, J=7.8, 6.4 Hz), 5.75 (1H, dd, J=15.9, 7.8 Hz),
6.10 (1H, d, J=15.9 Hz), 6.16 (1H, d, J=3.2 Hz), 6.35 (1H, dd,
J=3.2, 1.9 Hz), 7.32 (1H, d, J=1.9 Hz), 7.68 (1H, dd, J=8.3, 7.5
Hz), 8.19 (1H, brd, J=8.3 Hz), 8.42-8.47 (2H, m), 8.69 (1H, d,
J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 166
(N=2, Aryl=4-Fluorophenyl)
N-[2-(4-Fluoro-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamid
e
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.06 (3H, d, J=6.4 Hz),
1.3-2.0 (2H, br), 2.57-2.63 (2H, m), 2.95 (2H, t, J=5.5 Hz), 3.05
(1H, dq, J=8.0, 6.4 Hz), 5.72 (1H, dd, J=15.9, 8.0 Hz), 6.25 (1H,
d, J=15.9 Hz), 6.98 (2H, tm, J=8.7 Hz), 7.20-7.27 (2H, m), 7.68
(1H, dd, J= 8.1, 7.3 Hz), 8.18 (1H, brd, J=8.1 Hz), 8.42-8.47: (2H,
m), 8.69 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 167
(n=2, Aryl=4-Bromophenyl)
N-[2-(4-Bromo-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.06 (3H, d, J=6.4 Hz),
1.3-2.2 (2H, br), 2.56-2.63 (2H, m), 2.95 (2H, t, J=5.7 Hz), 3.05
(1H, dq, J=8.0, 6.4 Hz), 5.79 (1H, dd, J=15.9, 8.0 Hz), 6.22 (1H,
d, J=15.9 Hz), 7.13 (2H, dm, J=8.5 Hz), 7.41 (2H, dm, J=8.5 Hz),
7.68 (1H, dd, J=8.3, 7.4 Hz), 8.19 (1H, brd, J=8.3 Hz), 8.42-8.46
(2H, m), 8.69 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 168
(N=2, Aryl=4-Isopropylphenyl)
N-2-(4-Isopropyl-.alpha.-Methylcinnamylamino)ethyl]-5-Isoquinolinesulfonam
ide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.05 (3H, d, J=6.6 Hz),
1.24 (6H, d, J=6.8 Hz), 1.5-2.5 (2H, br), 2.56-2.63 (2H, m),
2.80-3.05 (3H, m), 5.74 (1H, dd, J=15.9, 8.0 Hz), 6.24 (1H, d,
J=15.9 Hz), 7.16 (2H, d, J=8.6 Hz), 7.20 (2H, d, J=8.6 Hz), 7.66
(1H, dd, J=8.3, 7.3 Hz), 8.17 (1H, brd, J=8.3 Hz), 8.43 (1H, dd,
J=7.3, 1.0 Hz), 8.44 (1H, d, J=6.1 Hz), 8.69 (1H, d, J=6.1 Hz),
9.34 (1H, d, J=1.0 Hz).
EXAMPLE 169
(n=2, Aryl=4-Methoxyphenyl)
N-2-(4-Methoxy-.alpha.-Methylcinnamylamino)ethyll-
5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.05 (3H, d, J=6.4 Hz),
1.5-2.5 (2H, br), 2.56-2.63 (2H, m), 2.96 (2H, t, J=5.6 Hz), 3.02
(1H, dq, J=8.0, 6.4 Hz), 3.81 (3H, s), 5.64 (1H, dd, J=15.9, 8.0
Hz), 6.21 (1H, d, J=15.9 Hz), 6.83 (2H, dm, J=8.8 Hz), 7.20 (2H,
dm, J=8.8 Hz), 7.67 (1H, dd, J=8.3, 7.3 Hz), 8.19 (1H, brd, J=8.3
Hz), 8.44 (1H, dd, J=7.3, 1.2 Hz), 8.44 (1H, d, J=6.1 Hz), 8.69
(1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).
EXAMPLE 170
(n=2, Aryl=4-Hydroxyphenyl)
N-[2-(4-Hydroxy-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonami
de
Colorless crystals;
Melting point: 70.degree.-73.degree. C.;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.06 (3H, d, J=6.4 Hz),
(2H, brt, J=5.7 Hz), 3.00 (2H, brt, J=5.7 Hz), 3.05 (1H, dq, J=8.0,
6.4 Hz), 3.3-3.5 (3H, br), 5.61 (1H, dd, J=15.9, 8.0 Hz), 6.19 (1H,
d, J=15.9 Hz), 6.75 (2H, brd, J=8.5 Hz), 7.10 (2H, brd, J=8.5 Hz),
7.65 (1H, dt, J=8.3, 7.3 Hz), 8.16 (1H, brd, J=Hz), 8.40-8.46 (2H,
m), 8.59 (1H, d, J=6.1 Hz), 9.32 (1H, d, J=1.0 Hz).
EXAMPLE 171
(N=3, Aryl=Phenyl)
N-[3-(.alpha.-Methylcinnamylamino)Propyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.27 (3H, d, J=6.6 Hz),
1.50-1.60 (2H, m), 1.6-2.5 (2H, br), 2.60-2.67 (2H, m), 3.01-3.09
(2H, m), 3.24 (1H, dq, J=7.8, 6.6 Hz), 5.91 (1H, dd, J=15.9, 7.8
Hz), 6.40 (1H, d, J=15.9 Hz), 7.30 (5H, m), 7.68 (1H, dd, J=8.0,
7.3 Hz), 8.18 (1H, brd, J=8.0 Hz), 8.43 (1H, dd, J=7.3, 1.2 Hz),
8.47 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.1 Hz), 9.36 (1H, d, J=1.0
Hz).
EXAMPLES 172 to 188
In Examples 172 to 188, the following general reaction was used.
##STR23##
EXAMPLE 172
(N=2, m=1, Aryl=4-Chlorophenyl)
N-[2-(4-Chlorocinnamylamino)ethyl]-5-Isoquinolinesulfonamide
2.01 g of N-(2-aminoethyl]-5-isoquinolinesulfonamide was dissolved
in 30 ml of methanol, to the solution was added 1.60 g of
p-chlorocinnamaldehyde, and the mixture was stirred for one hour at
a room temperature. After an addition of 350 mg of sodium
tetrahydrideborate in portions with ice cooling, the mixture was
stirred for 30 minutes. After an addition of ethyl acetate, the
reaction mixture was sequentially washed three times with water,
and then twice with a saturated sodium chloride aqueous solution,
and dried over magnesium sulfate. The mixture was filtered and
evaporated to remove the solvent under a reduced pressure. A
residue was purified using a silica gel column (silica gel 80 g,
eluant: 5% methanol in chloroform), and resulting crystals were
washed with benzene/hexane (1:1), to obtain 2.30 g of the title
compound as colorless crystals.
Melting point: 120.degree.-123.degree. C.;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8-3.5 (2H, br), 2.64-2.70
(2H, m), 2.97-3.03 (2H, m), 3.14 (2H, dd, J=6.1, 1.2 Hz), 6.00 (1H,
dt, J=15.9, 6.1 Hz), 6.32 (1H, d, J=15.9 Hz), 7.21 (2H, dd, J=8.8,
2.4 Hz), 7.28 (2H, dd, J=8.8, 2.4 Hz), 7.69 (1H, dd, J=8.3, 7.4
Hz), 8.19 (1H, dd, J=8.3, 1.0 Hz), 8.42-8.47 (2H, m), 8.69 (1H, d,
J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).
EXAMPLE 173
(N=2, M=1, Aryl=Phenyl)
N-(2-Cinnamylaminoethyl)-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8-2.8 (2H, br), 2.64-2.69
(2H, m), 2.97-3.03 (2H, m), 3.14 (1H, dd, J=6.3, 1.2 Hz), 6.02 (1H,
dt, J=15.9, 6.3 Hz), 6.46 (1H, dt, J=15.9, 1.2 Hz), 7.30 (5H, s),
7.68 (1H, dd, J=8.1, 7.3 Hz), 8.18 (1H, dt, J=8.1, 1.0 Hz),
8.42-8.48 (2H, m), 8.70 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0
Hz).
EXAMPLE 174
(N=2, M=1, Aryl=4-Dimethylaminophenyl)
N-2-(4-Dimetylaminocinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.65 (2H, brs), 2.70 (2H,
dd, J=6.1, 4,9 Hz), 2.96 (6H, s), 3.02 (2H, dd, J=6.1, 4.9 Hz),
3.14 (2H, dd, J=6.6, 1.0 Hz), 5.81 (1H, dt, J=15.9, 6.5 Hz), 6.27
(1H, brd, J=15.9 Hz), 6.66 (2H, brd, J=8.8 Hz), 7.20 (2H, brd,
J=8.8 Hz), 7.68 (1H, dd, J=8.0, 7.5 Hz), 8.18 (1H, dt, J=8.0, 1.0
Hz), 8.44 (1H, d, J=6.0 Hz and 1H, d, J=7.5 Hz), 8.71 (1H, d, J=6.1
Hz), 9.34 (1H, d, J=1.0 Hz}.
EXAMPLE 175
(N=2, M=1, Aryl= 4-Fluorophenyl)
N-[2-(4-Fluorocinnamylamino)ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5-2.5 (2H, br), 2.63-2.69
(2H, m), 2.97-3.02 (2H, m), 3.12 (2H, dd, J=6.1, 1.2 Hz), 5.94 (1H,
dt, J=15.9, 6.1 Hz), 6.33 (1H, d, J=15.9 Hz), 7.00 (2H, ddd, J=8.6,
8.6, 2.2 Hz), 7.27 (2H, ddd, J=8.6, 5.3, 2.2 Hz), 7.69 (1H, dd,
J=8.2, 7.6 Hz), 8.19 (1H, brd, J=8.2 Hz), 8.42-8.48 (2H, m), 8.70
(1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 176
(N=2, M=1, Aryl=4-Bromophenyl)
N-[2-(4-Bromophenylcinnamylamino)ethyl]-5-Isoquinolinesulfonamide
Colorless crystals;
Melting point: 124.degree.-127.degree. C.;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.0-3.5 (2H, br), 2.64-2.69
(2H, m), 2.97-3.03 (2H, m), 3.13 (2H, dd, J=6.1, 1.0 Hz), 6.01 (1H,
dt, J=15.9, 6.3 Hz), 6.30 (1H, d, J=15.9 Hz), 7.14 (2H, dm, J=8.6
Hz), 7.41 (2H, dm, J=8.6 Hz), 7.68 (1H, dd, J=8.3, 7.5 Hz), 8.18
(1H, brd, J=8.3 Hz), 8.43-8.47 (2H, m), 8.68 (1H, d, J=6.1 Hz),
9.34 (1H, d, J=1.0 Hz).
EXAMPLE 177
N=2, M=1, Aryl=4-Isopropylphenyl)
N-]2-(4-Isopropylcinnamylamino)ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.24 (6H, d, J=7.1 Hz),
2.0-2.3 (2H, br), 2.63-2.69 (1H, m), 2.87 (1H, q, J=7.1 Hz),
2.97-3.03 (2H, m), 3.13 (1H, dd, J=6.3, 1.2 Hz), 5.97 (1H, dt,
J=15.9, 6.3 Hz), 6.33 (1H, brd, J=15.9 Hz), 7.16 (2H, dm, J=8.3
Hz), 7.23 (2H, dm, J=8.3 Hz), 7.67 (1H, dd, J=8.3, 7.3 Hz), 8.17
(1H, d,
J=8.3 Hz), 8.43-8.47 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H, d,
J=1.0 Hz).
EXAMPLE 178
N=2, M=1, Aryl=4-Methoxyphenyl)
N-[2-(4-Methoxycinnamylamino)ethyl]-5-Isoquinolinesulfonamide
Colorless crystals;
Melting point: 92.degree.-95.degree. C.;
.sup.1 NMR (CDCl.sub.3, .delta. ppm): 2.0-3.0 (2H, br), 2.63-2.69
(2H, m), 2.97-3.06 (2H, m), 3.11 (2H, dd, J=6.3, 1.2 Hz), 3.81 (3H,
s), 5.88 (1H, dt, J=15.9, 6.3 Hz), 6.30 (1H, d, J=15.9 Hz), 6.84
(2H, dm, J=8.8 Hz), 7.23 (2H, dm, J=8.8 Hz), 7.68 (1H, dd, J=8.3,
7.5 Hz), 8.19 (1H, brd, J=8.3 Hz), 8.42-8.47 (2H, m), 8.69 (1H, d,
J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).
EXAMPLE 179
(N=2, M=1, Aryl=4-Trifluoromethylphenyl)
N-[2-(4-Trifluoromethylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5-2.5 (2H, br), 2.66-2.72
(2H, m), 2.98-3.04 (2H, m), 3.19 (2H, dd, J=6.1, 1.2 Hz), 6.14 (1H,
dt, J=15.9, 6.1 Hz), 6.41 (1H, d, J=15.9 Hz), 7.39 (2H, brd, J=8.3
Hz), 7.56 (2H, brd, J=8.3 Hz), 7.69 (1H, dd, J=8.3, 7.3 Hz), 8.20
(1H, brd, J=8.3 Hz), 8.42-8.48 (2H, m), 8.70 (1H, d, J=6.1 Hz),
9.35 (1H, d, J=1.0 Hz).
EXAMPLE 180
(N=2, M=2, Aryl=4-Trifluoromethylphenyl)
N-{2-[5-(4-Trifluoromethylphenyl)-2,4-Pentadienylamino]Ethyl}-5-Isoquinoli
nesulfonamide
Light yellow amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.0-2.5 (2H, br), 2.61-2.67
(2H, m), 2.96-3.05 (2H, m), 3.08 (2H, dd, J=6.3, 1.0 Hz), 5.69 (1H,
dt, J=15.0, 6.3 Hz), 6.19 (1H, dd, J=15.0, 10.0 Hz), 6.48 (1H, d,
J=15.7 Hz), 6.75 (1H, dd, J=15.7, 10.0 Hz), 7.47 (2H, brd, J=8.3
Hz), 7.57 (2H, brd, J=8.3 Hz), 7.72 (1H, dd, J=8.3, 7.3 Hz), 8.20
(1H, dt, J=8.3, 1.0 Hz), 8.43-8.48 (2H, m), 8.72 (1H, d, J=6.1 Hz),
9.36 (1H, d, J=1.0 Hz).
EXAMPLE 181
(N=2, M=3, Aryl=4-Trifluoromethylphenyl) N-{2
-[7-(4-Trifluoromethylphenyl)-2,4,6-Heptatrienylaminolethyl}-5-Isoquinolin
esulfonamide
Light yellow amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.0-3.5 (2H, br), 2.61-2.67
(2H, m), 2.95-3.01 (2H, m), 3.07 (2H, dd, J=6.3, 1.0 Hz), 5.59 (1H,
dt, J=14.6, 6.3 Hz), 6.05-6.22 (1H, m), 6.29-6.34 (2H, m), 6.55
(1H, d, J=5 6 Hz), 6.81-6.93 (1H, m), 7.47 (2H, brd, J=8.3 Hz),
7.55 (2H, brd, J=8.3 Hz), 7.71 (1H, dd, J=8.3, 7.3 Hz), 8.21 (1H,
brd, J=8.3 Hz), 8.43-8.48 (2H, m), 8.72 (1H, d, J=6.1 Hz), 9.37
(1H, d, J=1.0 Hz).
EXAMPLE 182
[N=2, M=1, Aryl=4-(2-Methoxyethoxy)Methoxyphenyl]N-{
2-[4-(2-Methoxyethoxy)Methoxycinnamylamino]Ethyl}-5-Isoquinolinesulfonamid
e
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.8-2.7 (2H, br), 2.63-2.69
(2H, m), 2.96-3.02 (2H, m), 3.11 (2H, dd, J=6.4, 1.2 Hz), 3.37 (3H,
s), 3.53-3.58 (2H, m), 3.80-3.85 (2H, m), 5.27 (2H, s), 5.90 (1H,
dt, J=15.9, Hz), 6.30 (1H, d, J=15.9 Hz), 6.99 (2H, dm, J=8.8 Hz),
7.23 (2H, dm, J=8.8 Hz), 7.68 (1H, dd, J=8.3, 7.3 Hz), 8.19 (1H,
dt, J=8.3, 1.0 Hz), 8.42-8.47 (2H, m), 8.70 (1H, d, J=6.1 Hz), 9.34
(1H, d, J=1.0 Hz).
EXAMPLE 183
(N=2, M=1, Aryl=4 -Hydroxyphenyl)
N-[2-(4-Hydroxycinnamylamino)ethyl]-5-Isoquinolinesulfonamide
Colorless crystals;
Melting point 156.degree.-159.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.44 (2H, brt, J=6.3 Hz),
2.88 (2H, brt, J=6.3 Hz), 3.01 (2H, brd, J=6.1 Hz), 3.39 (3H, br),
5.83 (1H, dt, J=15.9, 6.1 Hz), 6.20 (1H, d, J=15.9 Hz), 6.70 (2H,
brd, J=8.3 Hz), (2H, brd, J=8.3 Hz), 7.81 (1H, t, J=7.8 Hz),
8.34-8.46 (3H, m), 8.68 (1H, d, J=6.1 Hz), 9.46 (1H, d, J=1.0
Hz).
EXAMPLE 184
(N=2, M=1, Aryl=1-Naphthyl)
N-{2-[3-(1-Naphthyl)-2-Propenylamino]ethyl}-5-Isoquinolinesulfonamide
Colorless crystals;
Melting point: 135.degree.-138.degree. C.;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5 -.,4.0 (2H, br),
2.68-2.73 (2H, m), 3.01-3.06 (2H, m), 3.26 (1H, dd, J=3, 1.5 Hz),
6.00 (1H, dt, J=15.6, 6.3 Hz), 7.10 (1H, d, J=15.6 Hz), 7.43-7.51
(4H, m), 7.61 (1H, dt, J=8.3, 7.3 Hz), 7.78 (1H, dd, J=7.1, 2.7
Hz), 7.83-7.89 (1H, m), 7.97-8.02 (1H, m), 8.07 (1H, brd, J=8.3
Hz), 8.44 (1H, dd, J=7.3, 1.0 Hz), 8.44 (1H, d, J=6 1 Hz), 8.68
(1H, d, J=6.1 Hz), 9.27 (1H, d, J=1.0 Hz).
EXAMPLE 185
(N=2, M=1, Aryl= 3,4,5-Trimethoxyphenyl
N-[2-(3,4,5-Trimethoxycinnamylamino)ethyl]-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5-2.6 (2H, br), 2.65-2.71
(2H, m), 2.97-3.03 (2H, m), 3.15 (2H, dd, J=6.3, 1.2 Hz), 3.85 (3H,
s), 3.88 (6H, s), 5.97 (1H, dt, J=15.9, 6.3 Hz), 6.31 (1H, d,
J=15.9 Hz), 6.55 (2H, s), 7.69 (1H, dd, J=8.3, 7.5 Hz), 8.20 (1H,
brd, J=8.3 Hz), 8.43 (1H, brd, J=6.1 Hz), 8.46 (1H, dd, J=7.5, 1.2
Hz), 8.70 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0 Hz).
EXAMPLE 186
(N=2, M=1, Aryl=4-Methoxycarbonylphenyl)
N-[2-(4-Carbomethoxycinnamylamino)Ethyl-5-Isoquinolinesulfonamide
Colorless crystals;
Melting point 110.degree.-113.degree. C.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.2-2.0 (2H, br), 2.65-2.70
(2H, m), 2.97-3.02 (2H, m), 3.17 (2H, dd, J=5.9, 1.2 Hz), 3 92 (3H,
s), 6.15 (1H, dt, J=15.9, 5.9 Hz), 6.41 (1H, d, J=15.9 Hz), 7.36
(2H, dm, J=8.3 Hz), 7.69 (1H, dd, J=8.3, 7.3 Hz), 7.98 (2H, dm,
J=8.3 Hz), 8.19 (1H, brd, J=8.3 Hz), 8.43 (1H, brd, J=6.1 Hz), 8.46
(1H, dd, J=7.3, 1.5 Hz), 8.71 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0
Hz).
EXAMPLE 187
(N=2, M=1, Aryl=4-Carboxyphenyl) N-2-(4-Carboxycinnamylamino)Ethyl]
-5-Isoquinolinesulfonamide
Colorless crystals;
Melting points: 239.degree. to 240.degree. C. (decomposed);
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.49 (2H, brt, J=6.3 Hz),
2.91 (2H, brt, J=6.3 Hz), 3.13 (2H, brd, J=35 5.7 Hz), 3.0-4.0 (3H,
br), 6.24 (1H, dt, J=16.1, 5.7 Hz), 6.44 (1H, d, J=16.1 Hz), 7.44
(2H, brd, J=8.3 Hz), 7.82 (1H, dd, J=8.3, 7.3 Hz), 7.88 (2H, brd,
J=8.3 Hz), 8.36 (1H, dd, J=7.3, 1.2 Hz), 8.42 (1H, brd, J=8.3 Hz),
8.44 (1H, brd, J=6.1 Hz), 8.69 (1H, d, J=6.1 Hz), 9.46 (1H, d,
J=1.0 Hz)
EXAMPLE 188
(N=3, M=1, Aryl=Phenyl)
N-(3-Cinnamylaminopropyl)-5-Isoquinolinesulfonamide
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.5-2.2 (2H, br), 1.59 (2H,
tt, J=5.6, 5.6 Hz), 2.66 (2H, t, J=5.6 Hz), 3.06 (2H, t, J=5.6 Hz),
3.30 (2H, dd, J=6.1, 1.5 Hz), 6.21 (1H, dt, J=15.9, 6.1 Hz), 6.52
(1H, d, J=15.9 Hz), 7.21-7.40 (5H, m), 7.67 (1H, dd, J=8.3, 7.5
Hz), 8.18 (1H, d, J=8.3 Hz), 8.43 (1H, dd, J=7.5, 1.2 Hz), 8.44
(1H, d, J=6.1 Hz), 8.63 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0
Hz).
EXAMPLE 189
N-{2-[3-(4-Chlorophenyl)-2-Propynylamino]Ethyl}-5-Isoquinolinesulfonamide
(Compound 189-I; N-{
2-[Bis-(3-((4-Chlorophenyl))-2-Propynyl)Amino]Ethyl}-5-Isoquinolinesulfona
mide (Compound 189-II);
N-[3-(4-Chlorophenyl)-2-Propynyl]-N-[2-(P-Chloropheny)-2-Propynylamino]eth
yl]-5-Isoquinolinesulfonamide (Compound 189-III) ##STR24## 1.90 g
of N-(2-aminoethyl)-5-isoquinolinesulfonamide and 1.39 g of
3-p-chlorophenyl-2-propynyl chloride were dissolved in 10 ml of
dimethylformamide, to the solution was added 1.38 g of potassium
carbonate, and the mixture was stirred for 24 hours at a room
temperature. The reaction mixture was poured to 100 ml of ethyl
acetate, washed sequentially three times with water and then twice
with a saturated sodium chloride aqueous solution, dried over
magnesium sulfate, filtered, and evaporated to remove the solvent
under a reduced pressure. The resulting residue was separated and
purified using a silica gel column (silica gel 100 g; eluant: 5%
methanol/chloroform). By crystallizing from a mixture of
ether-hexane, 855 mg of compound 189-I as colorless crystals 220 mg
of compound 189-II, and 214 mg of compound 189-III in colorless
amorphous form were obtained.
Compound 189-I
Colorless crystals;
Melting point: 120.degree.-123.degree. C.;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.30-1.80 (2H, br),
2.74-2.80 (2H, m), 3.00-3.05 (2H, m), 3.39 (1H, s), 7.26 (4H, s),
7.69 (1H, dd, J=8.3, 7.3 Hz), 8.20 (1H, dt, J=8.3, 1.0 Hz), 8.42
(1H, dt, J=6.1, 1.0 Hz), 8.46 (1H, dd, J=7.3, 1.2 Hz), 8.70 (1H, d,
J=6.1 Hz), 9.36 (1H, d, J=1.0 Hz).
Compound 189-II
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.69-2.74 (2H, m),
3.01-3.09 (2H, m), 3.43 (4H, s), 5.48 (1H, t, J=5.0 Hz), 7.27 (4H,
dm, J=9.0 Hz), 7.30 (4H, dm, J=9.0 Hz), 7.68 (1H, dd, J=8.3, 7.3
Hz), 8.20 (1H, brd, J=8.3 Hz), 8.42 (1H, brd, J=6.1 Hz) , 8.47 (1H,
dd, J=7.3, 1.2 Hz), 8.66 (1H, d, J=6.1 Hz), 9.35 (1H, d, J=1.0
Hz).
Compound 189-III
Colorless amorphous form;
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.58 (1H, br), 3.02 (2H, t,
J=6.0 Hz), 3.55 (2H, t, J=6.0 Hz), 3.64 (2H, s), 4.50 (2H, s), 6.81
(2H, dm, J=8.8 Hz), 7.15 (2H, dm, J=8.8 Hz), 7.27 (2H, dm, J=9.0
Hz), 7.31 (2H, dm, J=9.0 Hz), 7.66 (1H, dd, J=8.3, 7.3 Hz), 8.13
(1H, brd, J=8.3 Hz), 8.48 (1H, dd, J=7.3, 1.2 Hz), 8.57 (1H, brd,
J=6.1 Hz), 8.69 (1H, d, J=6.1 Hz), 9.26 (1H, d, J=1.0 Hz).
EXAMPLE 190
N-[2-(4-Chloro-N-Methylcinnamylamino)ethyl]-5-Isoquinolinesulfonamide
##STR25##
1.50 g of the product of Example 172 was dissolved in 10 ml of
chloroform, to the solution was added 3 ml of methyl iodide at a
room temperature, and the mixture was stirred for 40 minutes.
Excess methyl iodide was immediately evaporated off under a reduced
pressure, and resulting residue was purified on a silica gel column
(silica gel 50 g, eluant: 5% methanol in chloroform), to obtain 720
mg of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 1.4-2.1 (1H, br), 1.95 (3H,
s), 2.37 (2H, t, J=5.5 Hz), 2.92-3.00 (3H, m), 5.97 (1H, dt,
J=15.9, 6.6 Hz), 6.34 (1H, d, J=15.9 Hz), 7.25 (2H, dm, J=8.8 Hz),
7.28 (2H, dm, J=8.8 Hz), 7.68 (1H, dd, J=8.3, 7.8 Hz), 8.19 (1H,
brd, J=8.3 Hz), 8.44 (1H, brd, J=6.1 Hz), 8.45 (1H, dd, J=7.8, 1.5
Hz), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H, d, J=1.0 Hz).
EXAMPLE 191
1-(4-Chlorocinnamyl)-4-(5-Isoquinolinesulfonyl)Piperazine
##STR26##
1.31 g of the product of Example 172 was dissolved in 3 ml of
dimethylformamide, to the solution were added 644 mg of
1,2-dibromoethane and 1.13 g of anhydrous potassium carbonate at a
room temperature, and the mixture was stirred for 24 hours. After
adding 100 ml of ethyl acetate, the ethyl acetate layer was
sequentially washed with water and a saturated sodium chloride
aqueous solution twice in each case, and dried over magnesium
sulfate. The solution was filtered and evaporated under a reduced
pressure, and resulting residue was purified on a silica gel column
(silica gel 50 g, eluant: 5% methanol in chloroform), to obtain 356
mg of the title compound in a colorless amorphous form, while
recovering the residual starting material.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.53 (4H, brt, J= 4.9 Hz),
3.10 (2H, dd, J=6.6, 1.2 Hz), 3.20 (4H, brt, J=4.9 Hz), 6.07 (1H,
dt, J=15.9, 6.6 Hz), 6.43 (1H, d, J=15.9 Hz), 7.24 (4H, s), 7.72
(1H, dd, J=8.1, 7.3 Hz), 8.22 (1H, brd, J=8.1 Hz), 8.37 (1H, dd,
J=7.3, 1.2 Hz), 8.55 (1H, brd, J=6.1 Hz), 8.68 (1H, d, J=6.1 Hz),
9.34 (1H, d, J=1.0 Hz).
EXAMPLE 192
N-Ethyl-N-[2-(4-Chloro-N-Ethylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamid
e ##STR27##
The procedure as described in Example 191 was repeated except that
1.31 g of the product of Example 172 and 2.14 g of ethyl iodide as
N-alkylating agent were used, to obtain 720 mg of the title
compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 0.99 (3H, t, J=7.1 Hz),
1.05 (3H, t, J=7.1 Hz), 2.53 (2H, q, J=7.1 Hz), 2.61 (2H, t, J=7.8
Hz), 3.19 (2H, dd, J=6.5, 1.2 Hz), 3.33-3.43 (4H, m), 6.12 (1H, dt,
J=15.9, 6.5 Hz), 6 32 (1H, d, J=15.9 Hz), 7.26 (4H, s), 7.62 (1H,
dd, J=8.1, 7.3 Hz), 8.14 (1H, dd, J=8.1 Hz), 8.35 (1H, dd, J=7.3,
1.2 Hz), 8.42 (1H, brd, J=6.1 Hz), 8.66 (1H, d, J=6.1 Hz), 9.31
(1H, d, J=1.0 Hz).
EXAMPLE 193
N-[2-(4-Chloro-N-Formylcinnamylamino)ethyl]-5-Isoquinolinesulfonamide
##STR28##
3 ml of formic acid and 3 ml of acetic anhydride were mixed and
stirred at a room temperature, and to the mixture was added 1.41 g
of the product of Example 172, and the mixture was stirred for one
hour. The reaction mixture was added to 50 ml of ethyl acetate and
30 ml of saturated sodium carbonate aqueous solution with ice, and
the mixture was stirred, and after foaming was terminated, the
ethyl acetate layer was sequentially washed twice with water and
once with a saturated sodium chloride aqueous solution, and dried
over magnesium sulfate, filtered and evaporated under a reduced
pressure. The resulting residue was purified on a silica gel column
(silica gel 60 g, eluant: 2% methanol in chloroform), to obtain
1.49 g of the title compound as a mixture of two isomers (3:2) in a
colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 3.07-3.16 (2H, m),
3.39-3.47 (2H, m), 3.90 (0.6 x 2H, dd, J=6.3, 1.0 Hz), 4.03 (0.4 x
2H, dd, J=6.3, 1.0 Hz), 5.93 (0.6H, dt, J=15.9, 6.3 Hz), 6.01
(0.4H, dt, J=15.9, 6.3 Hz), 6.40 (0.4H, d, J=15.9 Hz), 6.44 (0.6H,
d, J=15.9 Hz), 7.20 (0.6.times.2H, d, J=8.8 Hz), 7.21
(0.4.times.2H, d, J=8.8 Hz), 7.26 (0.6.times.2H, d, J=8.8 Hz), 7.27
(0.4.times.2H, d, J=8.8 Hz), 7.61 (0.6H, dd, J=8.0, 7.6 Hz), 7.64
(0.4H, dd, J=8.0, 7.6 Hz), 8.05 (0.6H, s), 8.09 (0.4 H, s), 8.16
(0.6H, brd, J=8.0 Hz), 8.17 (0.4H, brd, J=8.0 Hz), 8.33-8.42 (2H,
m), 8.60 (0.4H, d, J=6.1 Hz), 8.65 (0.6H, d, J=6.1 Hz), 9.33 (1H,
d, J=1.0 Hz).
EXAMPLE 194
N-{2-[4-Chloro-N-(4-Hydroxybenzyl)Cinnamylamino]ethyl}-5-Isoquinolinesulfon
amide
0.2 g of the product of Example 172 and 0.13 g of
p-hydroxybenzaldehyde were dissolved in 10 ml of methanol, to the
solution were added 60 mg of sodium cyanoborohydride and two drops
of acetic acid, and the mixture was stirred for 2 days at a room
temperature. The reaction mixture was concentrated under a reduced
pressure, and after adding a saturated sodium chloride aqueous
solution, extracted three times with 20 ml of ethyl acetate. The
extracts were combined, washed with sodium chloride, dried over
magnesium sulfate, filtered and concentrated under a reduced
pressure. The resulting residue was purified on a silica gel column
(silica gel 10 g, eluant: 2% methanol in chloroform), to obtain 150
mg of the title compound in a colorless amorphous form.
.sup.1 H-NMR (CDCl.sub.3, .delta. ppm): 2.50 (2H, brt), 2.90 (2H,
brt), 3.10 (2H, d, J=6.6 Hz), 3.35 (2H, s), 6.06 (1H, dt, J=15.6,
6.6 Hz), 6.35 (1H, d, J=15.9 Hz), 6.75 (2H, d, J=8.5 Hz), 6.97 (2H,
d, J=8.5 Hz), 7.30 (4H, s), 7.65 (1H, t, J=8.0 Hz), 8.15 (1H, d,
J=8.0 Hz), 8.37-8.41 (2H, m), 8.63 (1H, d, J=6.0 Hz), 9.32 (1H,
s).
EXAMPLE 195
2-Methyl-5-{[2-(4-Chloro-N,N-Dimethylcinnamylammonio)Ethyl]Aminosulfonyl}Is
oquinolium Diiodide
83 mg of the product of Example 172 was dissolved in 2.0 ml of
dimethylformamide, to the solution was added 1.0 ml of methyl
iodide, and the mixture was stirred for 4 hours at a room
temperature. Excess of methyl iodide and dimethylformamide were
evaporated off under a reduced pressure, and the resulting residue
was crystallized from 5 ml of a mixture of methanol/chloroform
(1:5). Crude crystals thus obtained was recrystallized from 10 ml
of a mixture of methanol/chloroform (1:5), to obtain 78 mg of the
title compound as light yellow crystals.
Melting point: 199.degree.-200.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 3.09 (6H, s), 3.43 (4H,
brs), 4.16 (2H, d, J=7.0 Hz), 4.53 (3H, s), 6.48 (1H, dt, J=15.9,
7.0 Hz), 6.89 (1H, d, J=15.9 Hz), 7.58 (2H, dm, J=9.4 Hz), 7.61
(2H, dm, J=9.4 Hz), 8.21 (1H, t, J=7.9 Hz), 8.72-8.78 (2H, m),
8.90-8.99 (3H, m), 10.22 (1H, brs).
EXAMPLE 196
2-Methyl-5-{N-Methyl-N-[2-(4-Chloro-N,N-Dimethylcinnamylammonio)Ethyl]Amino
sulfonyl}Isoquinolium Iodide
83 mg of the product of Example 172 was dissolved in 2.0 ml of
dimethylformamide, to the solution were added 1.0 ml of methyl
iodide and 83 mg of anhydrous sodium carbonate, and the mixture was
stirred for 4 hours at a room temperature. Excess methyl iodide and
dimethylformamide were evaporated off under a reduced pressure, and
after adding 10 ml of a mixture of methanol/chloroform (1:5) the
mixture was stirred, and then filtered to remove insoluble matter.
The filtrate was concentrated under a reduced pressure, and to the
concentrate was added 10 ml of a mixture of methanol/chloroform
(1:5) to precipitate an insoluble matter, which was then filtered
off. This concentration and filtration procedure was twice
repeated, to obtain 145 mg of the title compound in yellow
amorphous form.
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.97 (3H, s), 3.15 (6H,
s), 3.60-3.70 (2H, m), 3.70-3.80 (2H, m), 4.21 (2H, d, J=7.3 Hz),
4.54 (3H, s), 6.54 (1H, dt, J=15.6, 7.3 Hz), 6.93 (1H, d, J=15.6
Hz), 7.48 (2H, brd, J=8.5 Hz), 7.63 (2H, brd, J=8.5 Hz), 8.23 (1H,
t, J=7.9 Hz), 8.75-8.85 (3H, m), 8.99 (1H, d, J=7.1 Hz), 10.22 (1H,
brs).
The isoquinoline compounds other than that of Example 174 can be
treated with an excess amount of methyl iodide in
dimethylformamide, as described in this Example, to obtain
corresponding compounds wherein the nitrogen atom on the
isoquinoline ring has been methylated to a quaternary nitrogen
atom.
EXAMPLE 197
N-[2-(4-Chlorocinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Dihydrochloride
2.00 g of the product of Example 172 was suspended in 20 ml of
methanol, the suspension was made to a clear solution by adding 1
ml of concentrated hydrochloric acid, and stirred for 10 minutes
with ice cooling to form crystals. The crystals were collected by
filtration, and recrystallized from a mixture of 20 ml of methanol
and 3 ml of water to obtain 1.65 g of the corresponding
dihydrochloride as colorless crystals.
Melting point: 205.degree.-208.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.90-3.05 (2H, m),
3.10-3.20 (2H, m), 3.65-3.75 (2H, m), 4.3-4.9 (br), 6.33 (1H, dt,
J=16.1, 7.1 Hz), 6.76 (1H, d, J=16.1 Hz), 7.45 (4H, s), 8.00 (1H,
dd, J=8.3, 7.5 Hz), 8.54 (1H, dd, J=7.5, 1.2 Hz), 8.64 (1H, brd,
J=8.3 Hz), 8.71 (1H, brd, J=6.4 Hz), 8.80 (1H, br), 8.82 (1H, d,
J=6.4 Hz), 9.39 (1H, brs), 9.79 (1H, brs).
EXAMPLE 198
N-[2-(.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Dihydrochloride
The same procedure as described in Example 194 was repeated except
that the product of Example 154 was used as a starting material, to
obtain the corresponding dihydrochloride as colorless crystals.
Melting point: 80.degree.-85.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 1.40 (3H, d, J=6.5 Hz),
2.89 (2H, m), 3.16 (2H, brt, J=6.5 Hz), 3.91 (1H, m), 5.0-6.0 (br),
6.19 (1H, dd, J=16.1, 7.5 Hz), 6.71 (1H, d, J=16.1 Hz), 7.39 (5H,
m), 7.97 (1H, dd, J=8.0, 7.6 Hz), 8.51-8.82 (5H, m), 9.44 (2H, br),
9.76 (1H, d, J=1.0 Hz)
EXAMPLE 199
N-[2-(4-Chloro-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Dihydrochloride
The same procedure as described in Example 194 was repeated except
that the product of Example 153 was used as a starting material, to
obtain the corresponding dihydrochloride as a white hygroscopic
powder.
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 1.40 (3H, d, J=6.5 Hz),
2.85-3.96 (2H, m), 3.10-3.20 (2H, m), 3.80-4.00 (1H, m), 5.1-6.1
(br), 6.23 (1H, dd, J=15.9, 8.5 Hz), 6.72 (1H, d, J=15.9 Hz), 7.44
(4H, s), 7.99 (1H, dd, J=8.2, 7.4 Hz), 8.54 (1H, dd, J=7.4, 1.2
Hz), 8.64 (1H, brd, J=8.2 Hz), 8.72 (1H, brd, J=6.4 Hz), 8.80 (1H,
br), 8.82 (1H, d, J=6.4 Hz), 9.48 (2H, brs), 9.80 (1H, brs).
EXAMPLE 200
N-[2-(4-Bromocinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Dihydrochloride
The same procedure as described in Example 194 was repeated except
that the product of Example 176 was used a starting material, to
obtain the corresponding dihydrochloride as colorless crystals.
Melting point: 195.degree.-200.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.90-3.10 (2H, brs),
3.2-3.3 (2H, m), 3.65-3.75 (2H, brs), 6.35 (1H, dt, J=16.0, 7.1
Hz), 6.76 (1H, d, J=16.0 Hz), 7.38 (2H, d, J=8.5 Hz), 7.57 (2H, d,
J=8.5 Hz), 8.10 (1H, t, J=7.6 Hz), 8.67 (1H, d, J=7.6 Hz), 8.78
(1H, d, J=7.6 Hz), 8.90 (1H, brs), 9.05 (1H, brs), 10.0 (1H,
s).
EXAMPLE 201
N-(2-Cinnamylaminoethyl)-5-Isoquinolinesulfonamide.1/2 Fumarate
303 mg of the product of Example 173 was dissolved in 5 ml of ethyl
acetate, to the solution was added a solution of 89 ml of fumaric
acid in 2 ml of methanol at a room temperature, and the mixture was
stirred for minutes to from crystals, which was then collected by
filtration and washed with ethyl acetate to obtain mg of the
corresponding 1/2 fumarate as colorless crystals.
Melting point: 153.degree.-156.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 2.69 (2H, brt, J=6.3 Hz),
3.00 (2H, brt, J=6.3 Hz), 3.34 (2H, brd, J=6.1 Hz), 5.0-8.0 (3H,
br), 6.16 (1H, dt, J=16.0, 6.1 Hz), 6.51 (1H, d, J=16.0 Hz), 6.54
(1H, s), 7.23-7.3 (2H, m), 7.34-7.40 (3H, m), 7.82 (1H, dd, J=8.1,
7.5 Hz), 8.36 (1H, dd, J=7.5, 1.0 Hz), 8.42 (1H, brd, J=8.1 Hz),
8.44 (1H, brd, J=6.1 Hz), 8.69 (1H, d, J=6.1 Hz), 9.47 (1H, d,
J=1.0 Hz).
EXAMPLE 202
N-[2-(.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
1/2 Fumarate
The same procedure as described in Example 198 was repeated except
that the product of Example 154 was used as a starting material to
obtain the corresponding 1/2 fumarate as colorless crystals.
Melting point: 162.degree.-167.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 1.02 (3H, d, J=6.4 Hz),
2.49 (2H, brt, J=6.6 Hz), 2.5-5.7 (3H, br), 2.93 (2H, brt, J=6.6
Hz), 3.17 (1H, dd, J=7.9, 6.4 Hz), 5.91 (1H, dd, J=16.1, 7.9 Hz),
6.35 (1H, d, J=16.1 Hz), 6.55 (1H, s), 7.32 (5H, m), 7.79 (1H, dd,
J=8.0, 7.3 Hz), 8.34 (1H, dd, J=7.3, 1.2 Hz), 8.39 (1H, brd, J=8.0
Hz), 8.43 (1H, brd, J=6.1 Hz), 8.69 (1H, d, J=6.1 Hz), 9.45 (1H, d,
J=1.0 Hz).
EXAMPLE 203
N-[2-(4-Chloro-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
L-(+)-tartrate
6.60 g of the product of Example 153 was dissolved in 50 ml of
ethyl acetate, to the solution was added a solution of 2.38 g of
L-(+)-tartaric acid in methanol to form crystals, which was then
collected by filtration and washed with ethyl acetate to obtain the
corresponding L-(+)-tartrate as colorless crystals.
Melting point: 125-130.degree. C.;
.sup.1 H-NMR (DMSO-d.sub.6, .delta. ppm): 1.14 (3H, d, J=6.3 Hz),
2.64 (2H, brt, J=6.5 Hz), 2.98 (2H, brt, J=6.5 Hz), 3.45 (1H, dd,
J=8.0, 6.3 Hz), 3.5-4.7 (6H, br), 4.13 (2H, s), 6.03 (1H, dd,
J=15.9, 8.0 Hz), 6.49 (1H, d, J=15.9 Hz), 7.41 (4H, s), 7.81 (1H,
dd, J=8.0, 7.3 Hz), 8.36 (1H, brd, J=8.0 Hz), 8.41 (1H, d, J=6.1
Hz), 8.42 (1H, brd, J=7.3 Hz), 8.69 (1H, d, J=6.1 Hz), 9.46 (1H, d,
J=1.0 Hz).
EXAMPLE 204
N-(2-Aminoethyl)-N-(2-Cinnamylaminoethyl)-5-Isoquinolinesulfonamide
Trihydrochloride
To a solution of 1.10 g of the amorphous compound obtained in
Example 173, 1.18 g of triphenylphosphine and 0.73 g of
2-(tert-butoxycarbonylamino)ethanol in 15 ml of tetrahydrofuran,
was added dropwise a solution of 0.78 g of diethyl azodicarboxylate
in 5 ml of tetrahydrofuran for 15 ml with ice cooling, and the
mixture was stirred for 4 hours at a room temperature. After again
ice-cooling, to the reaction mixture was added 0.39 g of
triphenylphosphine, and added dropwise a solution of 0.26 g of
diethylazodicarbox.ylate in 3 ml of tetrahydrofuran, and the
reaction mixture was stirred at a room temperature for one hour.
The reaction mixture was concentrated under a reduced pressure, and
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (19:1), to obtain 0.99 g of a light orange
amorphous product. The product was dissolved in 20 ml of methanol,
to the solution was added 7.7 ml of 4N hydrochlonic acid in ethyl
acetate, and the mixture was stirred at a room temperature for 3
hours. The reaction mixture was evaporated to remove the solvent
under a reduced pressure, and thereto was added ethyl acetate to
form a solid. The solid was collected by filtratoin, washed with
ethyl acetate and n-hexane, and dried under a reduced pressure to
obtain 0.97 g of the title compound as a colorless hygroscopic
powder.
NMR (D.sub.2 O) .delta. ppm: 3.2-3.5 (4H, m), 3.7-4.0 (6H, m),
6.1-6.3 (1H, m), 6.82 (1H, d, J=15.9 Hz), 7.44 (5H, s), 8.15 (1H,
t, J=7.6 Hz), 8.1-8.3 (3H, m), 9.09 (1H, d, J=7.0 Hz), 9.7 (1H,
s).
EXAMPLE 205
N-(4-Aminobutyl)-N-[2-(4-Chlorocinnamylamino)Ethyl]-5-Isoquinolinesulfonami
de Trihydrochlorides
To a solution of 0.4 g of the crystals obtained in Example 172.
0.226 g of 4-(tert-butoxycarbonylamino)butanol and 0.445 g of
triphenylphosphine in 5 ml of tetrahydrofuran, was added a solution
of 0.295 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran
with stirring under ice cooling. The mixture was allowed to stand
at room temperature, and evaporated under a reduced pressure to
obtain a residue, which was then applied to a silica gel column and
eluted with methanol/chloroform (2:98) to obtain 0.28 g of oil. To
a solution of the oil in 1 ml of methanol, as added 4N hydrochloric
acid/ethyl acetate to form a precipitate, which was then collected
by filtration, washed with ethyl acetate and dried to obtain 0.2 g
of the title compound as a colorless powder.
NMR (D.sub.2 O) .delta. ppm: 1.70 (4H, brs), 2.95 (2H, m), 3.30
(2H, m), 3.55 (2H, m), 3.77 (2H, m), 3.89 (2H, dd, J=7.3 Hz), 6.15
(1H, dt, J=15.8, 7.3 Hz), 6.76 (1H, d, J=15.8 Hz), 7.35 (4H, s),
8.11 (1H, t, J=8.0 Hz), 8.6-8.8 (2H, m), 8.98 (1H, d, J=7.0 Hz),
9.75 (1H, s).
EXAMPLE 206
N-[2-(4-Chloro-N-Methylcinnamylamino)ethyl]-N-[2-(4-Piperidyl)ethyl]-5-Isoq
uinolinesulfoneamide
To a solution of 0.39 g of the amorphous compound obtained in
Example 190, 0.145 g of 4-piperidinethanol and 0.265 g of
triphenylphosphine in 5 ml of tetrahydrofuran, was added a solution
of 0.245 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran
with ice cooling, and the mixture was stirred for one hour at a
room temperature and evaporated to remove the solvent under a
reduced pressure. After an addition of 30 ml of ethyl acetate, the
mixture was extracted three times with 5 ml of 1N hydrochloric
acid. The extract was alkalized with sodium bicarbonate and
extracted three times with 10 ml of ethyl acetate. The organic
layer was dried over magnesium sulfate and evaporated to remove the
solvent. The resulting residue was applied to an almina
chromatographic column and eluted with 1% methanol in chloroform to
obtain 180 mg of the title compound as colorless oil.
NMR (CDCl.sub.3) .delta. ppm: 0.87-1.05 (2H, m), 1,30-1.45 (5H, m),
1.85 (1H, brs), 2.21 (3H, s), 2.33 (2H, m), 2.51 (2H, t, J=7.6 Hz),
2.89 (2H, m), 3.08 (2H, d, J=6.6 Hz), 3.30 (2H, t, J=7.8 Hz), 3.42
(2H, t, J=7.3 Hz), 6.09 (1H, dt, J=15.8, 6.6 Hz), 6.41 (1H, d, J=
15.8 Hz), 7.26 (4H, s), 7.65 (1H, dd, J=8.0, 8.6 Hz), 8.15 (1H, d,
J=8.0 Hz), 8.4 (1H, d, J=8.6 Hz), 8.40 (1H, d, J=6.1 Hz), 8.67 (1H,
d, J=6.1 Hz), 9.31 (1H, s).
The oil thus obtained was dissolved in 1 ml of methanol, and
thereto were added 0.3 ml of 4N hydrochlonic acid in ethyl acetate
and then 30 ml of ether, to obtain the corresponding
trihydrochloride as colorless powder.
EXAMPLE 207
N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl]-N-[2-Morpholinoethyl)-5-Isoquin
olinesulfonamide Trihydrochloride
To a solution of 1 g of the amorphous compound obtained in Example
190, 0.377 g of 2-N-morpholinoethanol and 1.25 g of
triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a
solution of 0.835 g of diethyl azodicarboxylate in 2 ml of
tetrahydrofuran with stirring under ice cooling, and the mixture
was stirred for 2 hours. After evaporating off the solvent under a
reduced pressure, to the residue was added 20 ml of ethyl acetate,
and the mixture was extracted three times with 10 ml of 1N
hydrochloric acid. The extract was alkalized with sodium
bicarbonate and extracted three times with 10 ml of ethyl acetate.
The extract was dried over magnesium sulfate and evaporated under a
reduced pressure to remove the solvent. The resulting residue was
applied to a silica gel column and eluted with methanol/ethyl
acetate (10:90) to obtain an oil.
NMR (CDCl.sub.3) .delta. ppm: 2.18 (3H, s), 2.28-2.33 (4H, m), 2.4
(2.6 (4H, m), 3.07 (2H, d, J=6.6 Hz), 3.4-3.6 (8H, m), 6.07 (1H,
dt, J=15.9, 6.6 Hz), 6.40 (1H, d, J=15.9 Hz), 7.26 (4H, s), 7.63
(1H, dd, J=8.0, 7.1 Hz), 8.14 (1H, d, J=8.0 Hz), 8.42 (1H, d, J=7.1
Hz), 8.42 (1H, d, J=7.1 Hz), 8.42 (1H, d, J=6.1 Hz), 8.67 (1H, d,
J=6.1 Hz), 9.31 (1H, s].
The oil thus obtained was dissolved 4 ml of methanol, and was added
in 2 ml of 4N hydrochloric acid in ethyl acetate, and the solvent
was evaporated to remove the solvent under a reduced pressure, the
resulting product was recrystallized from ethanol to obtain 0.67 of
the title compound as colorless crystals.
Melting point: 172.degree.-176.degree. C.;
NMR (D.sub.2 O) .delta. ppm: 3.04 (3H, s), 3.2-3.6 (8H, m), 3.8-4.1
(10H, m), 6.18 (1H, dt, J=15.9, 7.0 Hz), 6.76 (1H, d, J=15.9 Hz),
7.22 (4H, s), 8.09 (1H, dd, J=7.6, 8.2 Hz), 8.52 (1H, d, J=7.6 Hz),
8.65-8.75 (2H, m), 8.87 (1H, d, J=7.0 Hz), 9.74 (1H, s).
EXAMPLE 208
N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl]-N-(2-Piperidinoethyl)-5-Isoquin
olinesulfonamide
To a solution of 0.39 g of the amorphous compound obtained in
Example 190, 0.145 g of 1-piperidinethanol and 0.369 g of
triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a
solution of 0.245 g of diethyl azodicarboxylate in 2 ml of
tetrahydrofuran with stirring under ice cooling. The mixture was
stirred for 2 hours and evaporated to remove the solvent under a
reduced pressure, and resulting residue dissolved in 30 ml of ethyl
acetate and extracted three times with 10 ml of 1N hydrochloric
acid. The aqueous layer was alkallized with sodium bicarbonate and
extracted three times with 10 ml of ehtyl acetate, and the organic
extract was dried over magnesium sulfate and evaporated to remove
the solvent at a reduced pressure. The resulting residue was
applied to a silica gel column and eluted with 2% methanol in
chloroform, to obtain 0.37 g of the title compound as a colorless
oil.
NMR (CDCl.sub.3) .delta. ppm: 1.3-1.5 (6H, m), 2.20 (3H, s),
2.20-2.30 (4H, m), 2.39 (2H, t, J=7.1 Hz), 2.55 (2H, t, J=7.1 Hz),
3.08 (2H, d, J=6.8 Hz), 3.46 (4H, q, J=7.1 Hz), 6.09 (1H, dt,
J=15.9, 6.8 Hz), 6.40 (1H, J=15.9 Hz), 7.25 (4H, s), 7.63 (1H, dd,
J=7.3, 8.1 Hz), 8.14 (1H, d, J=8.1 Hz), 8.43 (1H, d, J=7.3 Hz),
8.43 (1H, d, J=6.1 Hz), 8.67 (1H, d, J=6.1 Hz), 9.31 (1H, s).
To a solution of above-obtained oil in 3 ml of methanol, was added
0.5 ml of 4N hydrochloric acid in ethyl acetate, and the whole was
evaporated to remove the solvent under a reduced pressure. To the
concentrate was added ether to form powder, which was then
collected by filtration to obtain 0.35 g of the corresponding
trihydrochloride as a colorless powder.
NMR (D.sub.2 O) .delta. ppm: 1.3-2.0 (6H, m), 2.8-3.0 (2H, m), 3.05
(3H, s), 3.3-3.6 (6H, m), 3.8-4.1 (6H, m), 6.25 (1H, dt, J=15.8,
8.0 Hz), 6.80 (1H, d, J=15.8 Hz), 7.25 (4H, s), 8.13 (1H, t, J=8.0
Hz), 8.60 (1H, d, J=8.0 Hz), 8.68-8.78 (2H, m), 8.95 (1H, d, J=7.0
Hz), 9.70 (1H, s).
EXAMPLE 209
N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl-N-(2-Dimethylaminoethyl)-5-Isoqu
inolinesulfonamide
To a solution of 1.0 g of the amorphous compound obtained in
Example 190, 0.267 g of 2-dimethylamino ethanol and 0.982 g of
triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a
solution of 0.652 g of diethyl azodicarboxylate in 2 ml of
tetrahydrofuran with stirring under ice cooling. After 2 hours, the
reaction mixture was concentrated under a reduced pressure to
remove tetrahydrofuran, and resulting residue was dissolved in 10
ml of ethyl acetate and extracted three times with 10 ml of 1N
hydrochloric acid. The aqueous layer was alkalized with sodium
bicarbonate and extracted three times with 10 ml of ethyl acetate,
and the organic layer was dried over magnesium sulfate and
evaporated to removed the solvent under a reduced pressure. The
resulting residue was then applied to a silica gel column and
eluted with 3% methanol in chloroform, to obtain 0.77 g of the
title compound as a colorless oil.
NMR (CDCl.sub.3) , .delta. ppm: 2.11 (6H, s), 2.20 (3H, s), 2.38
(2H, t, J=7.3 Hz), 2, t, 54 (2H, t, J=7.3 Hz), 3.08 (2H, d, J=6.6
Hz), 3.38-3.50 (4H, m), 6.08 (1H, dt, J=15.8, 6.6 Hz), 6.40 (1H, d,
J=15.8 Hz), 7.26 (4H, s), 7.63 (1H, dd, J=8.1, 7.5 Hz), 8.14 (1H,
d, J=8.1 Hz), 8.40-8.45 (2H, m), 8.68 (1H, d, J=6.1 Hz), 9.31 (1H,
s).
To a solution of the oil thus obtained in 5 ml of methanol was
added 1.4 ml of 4N hydrochloric acid in ethyl acetate, and after
evaporating off the solvent under a reduced pressure, to the
resulting concentrate was added ether to form powder, which was
then collected by filtration and dried to obtain 0.7 g of the
corresponding trihydrochloride as a powder.
NMR (D.sub.2 O) .delta. ppm: 2.96 (6H, s), 3.03 (3H, s), 3.4-3.6
(4H, m), 3.9-4.1 (6H, m), 6.17 (1H, dt, J=15.9, 7.0 Hz), 6.73 (1H,
d, J=15.9 Hz), 7.19 (4H, s), 8.01 (1H, t, J=8.0 Hz), 8.54 (1H, d,
J=8.0 Hz), 8.70 (2H, m), 8.91 (1H, d, J=8.0 Hz), 9.78 (1H, s).
EXAMPLE 210
N-(2-Piperidinoethyl)-N-[2-(N-Methylcinnamylamino)Ethyl]-5-Isoquinolinesuli
onamide
The amorphous product obtained in Example 173 was treated according
to the procedure described in Example 190, to obtain
N-[2-(N-methylcinnamylamino)ethyl]-5-isoquinolinesulfonamide.
NMR (CDCl.sub.3) .delta. ppm: 1.95 (3H, s), 2.37 (2H, t, J=5.7 Hz),
2.93-3.00 (4H, m), 6.00 (1H, dt, J=15.8, 6.6 Hz), 6.38 (1H, d,
J=15.8 Hz), 7.31 (5H, s), 7.68 (1H, dd, J=8.3, 7.3 Hz), 8.18 (1H,
d, J=8.3 Hz), 8.43-8.47 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.34 (1H,
s).
To a solution of 0.476 g of the above compound, 0.193 g of
1-piperidinethanol and 0.524 g of triphenylphosphine in 5 ml of
tetrahydrofuran, was added a solution of 0.348 g of diethyl
azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice
cooling, and the mixture was allowed to stand for 3 hours and
evaporated to remove the solvent under a reduced pressure. To the
concentrate was added 30 ml of ethyl acetate, and the mixture was
extracted three times with 10 ml of 1N hydrochloric acid. The
extract was alkalized with sodium bicarbonate and extracted three
times with 10 ml of ethyl acetate. The ethyl acetate solution was
dried over magnesium sulfate and evaporated under a reduced
pressure to remove the solvent. The resulting residue was applied
to a silica gel column and eluted with 5% methanol in chloroform,
to obtain 0.44 g of the title compound as colorless oil.
NMR (CDCl.sub.3) .delta. ppm: 1.3-1.5 (6H, m), 2.20 (3H, s),
2.20-2.30 (4H, m), 2.41 (2H, t, J=6.8 Hz), 2.53 (2H, t, J=6.3 Hz),
3.09 (2H, d, J=6.6 Hz), 3.4-3.55 (4H, m), 6.10 (1H, dt, J=15.8, 6.6
Hz), 6.45 (1H, d, J=15.8 Hz), 7.2-7.4 (5H, m), 7.61 (1H, dd, J=8.0,
7.5 Hz), 8.11 (1H, d, J=8.0 Hz), 8.4-8.5 (2H, m), 8.66 (1H, d,
J=6.1 Hz), 9.29 (1H, s).
To the oil thus obtained in 5 ml of methanol was added 0.8 ml of 4N
hydrochloric acid in ethyl acetate, and the solution was evaporated
to remove the solvent under a reduced pressure. A precipitate
obtained by addition of 50 ml of ether was collected by filtration
and dried to obtain 0.4 g of the corresponding trihydrochloride as
a colorless powder.
NMR (D.sub.2 O) .delta. ppm: 1.6-2.0 (6H, m), 2.7-2.9 (2H, m), 3.04
(3H, s), 3.4-3.6 (6H, m), 3.9-4.1 (6H, m), 6.25 (1H, dt, J=15.8,
8.0 Hz), 6.86 (1H, d, J=15.8 Hz), 7.40 (5H, s), 8.14 (1H, t, J=8.0
Hz), 8.6-8.7 (3H, m), 9.0 (1H, d, J=7.0 Hz), 9.72 (1H, s).
EXAMPLE 211
N-Anisyl-N-[2-(4-Chlorocinnamylamino)Ethyl-5-Isoquinolinesulfonamide
0.4 g of the crystals obtained in Example 172, 0.276 g of anisyl
alcohol and 0.524 g of triphenylphosphine were dissolved in 10 ml
of tetrahydrofuran, and to the solution was added dropwise a
solution of 0.404 g of diisopropyl azodicarboxylate in 2 ml of
tetrahydrofuran with stirring under ice cooling. The reaction
mixture was warmed to a room temperature and was allowed to stand
overnight and then evaporated under a reduced pressure to remove
the solvent. The resulting residue was dissolved in 30 ml of ethyl
acetate, and the mixture was extracted twice with 30 ml of 1N
hydrochloric acid. The extract was alkalized with sodium
bicarbonate and extracted twice with 30 ml of ethyl acetate. The
ethyl acetate solution was washed with water, dried over magnesium
sulfate and evaporated under a reduced pressure to remove the
solvent. The resulting residue was applied to a silica gel column
and eluted with 1% methanol in chloroform, to obtain 0.22 g of the
title compound as a colorless oil.
NMR (CDCl.sub.3) .delta. ppm: 2.61 (2H, t, J=6.0 Hz), 3.14 (2H, d,
J=6.1 Hz), 3.34 (2H, t, J=6.6 Hz), 3.74 (3H, s), 4,43 (2H, s), 6.0
(1H, dt, J=15.9, 6.1 Hz), 6.30 (1H, d, J=15.9 Hz), 6.75 (2H, d,
J=8.8 Hz), 7.08 (2H, d, J=8.8 Hz), 7.26 (4H, s), 7.66 (1H, dd,
J=8.3, 7.3 Hz), 8.17 (1H, brd, J=8.3 Hz), 8.39-8.49 (2H, m), 8.69
(1H, d, J=6.1 Hz), 9.3 (1H, s).
EXAMPLE 212
N-[2-(4-Chlorocinnamylamino)Ethyl]-N-Phenethyl-5-Isoquinolinesulfonamide
The procedure described in Example 211 was repeated except that
0.146 g of phenethyl alcohol was used in place of anisyl alcohol,
to obtain 0.37 g of the title compound as a colorless oil.
NMR (CDCl.sub.3) .delta. ppm: 1.4 (1H, brs), 2.75-2.90 (4H, m),
3.27 (2H, d, J=6.1 Hz), 3,4-3.6 (4H, m), 6.10 (1H, dt, J=15.9, 6.1
Hz), 6.39 (1H, d, J=15.9 Hz), 6.59-7.05 (2H, m), 7.1-7.2 (3H, m),
7.26 (4H, s), 7.65 (1H, dd, J=8.3, 7.6 Hz), 8.15 (1H, d, J=8.3 Hz),
8.38 (2H, t, J=6.1 Hz), 8.63 (1H, d, J=6.1 Hz), 9.28 (1H, s).
EXAMPLE 213
N-Benzyl-N-[2-(4-Chlorocinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
The procedure described in Example 211 was repeated except that
0.162 g of benzyl alcohol was used in place of anisyl alcohol, to
obtain 0.3 g of the title compound as a colorless oil.
NMR (CDCl.sub.3) .delta. ppm: 2.0 (1H, brs), 2.6 (2H, t, J=6.6 Hz),
3.15 (2H, d, J=6.1 Hz), 3.40 (2H, t, J=6.6 Hz), 4.50 (2H, s), 6.0
(1H, dt, J=15.8, 6.1 Hz), 6.30 (1H, d, J=15.8 Hz), 7.15-7.25 (9H,
m), 7.66 (1H, dd, J=8.0, 7.6 Hz), 8.16 (1H, d, J=8.0 Hz), 8.4-8.5
(2H, m), 8.70 (1H, d, J=6.1 Hz), 9.31 (1H, s).
EXAMPLE 214
N-[2-(4-Chlorocinnamylamino)Ethyl]-N-Methyl-5-Isoquinolinesulfonamide
The procedure described in Example 211 was repeated except that 48
mg of methanol was used in place of anisyl alcohol, to obtain 0.3 g
of the title compound as a colorless oil.
NMR (CDCl.sub.3) .delta. ppm: 1.5 (1H, brs), 2.86 (2H, t, J=6.2
Hz), 2.88 (3H, s), 3.3-3.4 (4H, m), 6.15 (1H, dt, J=15.8, 6.1 Hz),
6.43 (1H, d, J=15.8 Hz), 7.27 (4H, s), 7.69 (1H, dd, J=8.3, 7.3
Hz), 8.18 (1H, d, J=8.3 Hz), 8.38 (1H, d, J=7.3 Hz), 8.50 (1H, d,
J=6.3 Hz), 8.67 (1H, d, J=6.3 Hz), 9.31 (1H, s).
REFERENCE EXAMPLE 45
N-(3,4-Dimethoxyphenyl)-5-Isoquinolinesulfonamide
3.06 g of 3,4-dimethoxyaniline was dissolved in 30 ml of pyridine,
to the solution was added in small portions 5.28 g of
5-isoquinolinesulfonyl chloride.HCl with stirring under ice
cooling, and the mixture was stirred for 30 minutes, and further
stirred at a room temperature overnight. After evaporating off the
pyridine under a reduced pressure and additing 20 ml of water, the
mixture was extracted twice with 50 ml of chloroform/isopropanol
(10:1). The extract was dried over magnesium sulfate and evaporated
under a reduced pressure to remove the solvent. To the resulting
residue was added 20 ml of benzene/chloroform (3:1), and the
mixture was slightly warmed and collected to obtain 5.64 g of the
title compound as colorless crystals.
Melting point: 195.degree.-197.degree. C.;
NMR (CDCl.sub.3) .delta. ppm: 3.67 (3H, s), 3.77 (3H, s), 6.3 (1H,
dd, J=8.5, 2.7 Hz), 6.5-6.6 (3H, complex), 7.61 (1H, t, J=8.3 Hz),
8.2 (1H, d, J=8.3 Hz), 8.3 (1H, dd, J=1.3, 7.3 Hz), 8.4 (1H, d,
J=6.1 Hz), 8.7 (1H, d, J=6.4 Hz), 9.36 (1H, d, J=1.3 Hz).
REFERENCE EXAMPLE 46
N-(3,4-Dimethoxyphenyl)-N-(2-Phthalimidethyl)-5-Isoquinolinesulfonamide
500 mg of the crystals obtained in Reference Example 45 was
dissolved in 7 ml of dimethylformamide and 4 ml of tetrahydrofuran,
to the solution was added 70 mg of 60% sodium hydride with stirring
under ice cooling, and the mixture was stirred for 20 minutes, and
fter adding 406 mg of bromoethylphthalimide, the whole was refluxed
for 6 hours with stirring. After adding 10 ml of ice water, the
reaction mixture was extracted with 30 ml of ethyl acetate, and the
extract was dried over magnesium sulfate and evaporated under a
reduced pressure to remove the solvent. The resulting residue was
applied to a silica gel column and eluted with chloroform/methanol
(100:1) to obtain 320 mg of the title compound as colorless
crystals.
Melting Point: 197.degree.-201.degree. C.;
NMR (CDCl.sub.3) .delta. ppm: 3.80 (3H, s), 3.88 (3H, s), 3.7-3.78
(2H, complex), 3.75-4.0 (2H, complex), 6.67 (1H, s), 6.68 (1H, s),
6.73 (1H, s), 7.57 (1H, t, J=7.57 Hz), 7.73 (4H, s), 8.0 (1H, dd,
J=1.0, 8.3 Hz), 8.05 (1H, d, J=7.3 Hz), 8.24 (1H, dd, J=1.0, 7.57
Hz), 8.44 (1H, brd), 9.1 (1H, brs).
REFERENCE EXAMPLE 47
N-(3,4-Dimethoxvphenyl)-N-(2-Aminoethyl)-5-Isoquinolinesulfonamide
517 mg of the crystals obtained in Reference Example 46 was
dissolved in 5 ml of methanol and 5 ml of chloroform, to the
solution was added 60 mg of hydrozine hydrate, and the mixture was
refluxed for 3 hours. Crystallized insoluble matter was filtered
off, and the filtrate was evaporated under a reduced pressure to
remove the solvent. After an addition of 10 ml of ethyl acetate,
the whole was filtered to remove the insoluble matter and then
evaporated under a reduced pressure to yield 420 mg of the title
compound obtained as a slightly yellow oil.
NMR (CDCl.sub.3) .delta. ppm: 2.76 (2H, t, J=6.1 Hz), 3.60 (3H, s),
3.75 (2H, t, J=6.1 Hz), 3.83 (3H, s), 6.48 (1H, s), 6.46 (1H, d,
J=9.2 Hz), 6.63 (1H, d, J=9.2 Hz), 7.61 (1H, t, J=7.5 Hz), 8.18
(1H, d, J=8.0 Hz), 8.25 (1H, dd, J=1.3, 8.3 Hz), 8.5 (1H, d, J=6.1
Hz), 9.3 (1H, d, J=1.3 Hz).
EXAMPLE 215
N-(3,4-Dimethoxyphenyl)-N-[2-(4-Chlorocinnamylamino)Ethyl]-5-Isoquinolinesu
lfonamide
320 mg of the oil obtained in Reference Example 47 was dissolved in
6 ml of dimethylformamide, to the solution were added 200 mg of
potassium carbonate and 150 mg of p-chlorocinnamyl chloride, and
the mixture was stirred overnight at a room temperature. After
adding 20 ml of water the reaction mixture was extracted twice with
30 ml of chloroform. The extract was washed with a saturated sodium
chloride aqueous solution, dried over magnesium chloride and
evaporated under a reduced pressure to remove the solvent. The
resulting residue was applied to a silica gel column and eluted
with chloroform/methanol (100:1) to obtain 90 mg of the title
compound as colorless crystals.
NMR (CDCl.sub.3) .delta. ppm: 2.75 (2H, t, J=6.1 Hz), 3,36 (1H, d,
J=6.1 Hz), 3.6 (3H, s), 3.74 (2H, d, J=6.1 Hz), 3.82 (3H, s), 6.15
(1H, d, and dt, J=15.6, 6.1 Hz), 6.42 (1H, d, J=15.6 Hz), 6.5 (1H,
s), 6.61 (1H, d, J=8.1 Hz), 6.48 (1H, d, J=6.1 Hz), 7.3 (4H, brs),
7.63 (1H, t, J=8.1 Hz), 8.16 (1H, d, J=6.1 Hz), 8.17 (1H, d, J=8.1
Hz), 8.3 (1H, dd, J=1.0, 6.1 Hz), 8.5 (1H, d, J=6.1 Hz), 9.3 (1H,
d, J=1.0 Hz).
EXAMPLE 216
N-{2-[Bis(4-Chlorocinnamyl)Amino]Ethyl}-5-Isoquinolinesulfonamide
In Example 215, prior to elution using chloroform/methanol, elution
was carried out using chloroform to obtain 100 mg of the title
compound in a colorless amorphous form.
NMR (CDCl.sub.3) .delta. ppm: 2.66 (2H, t, J=6.2 Hz), 3.25 (4H, d,
J=6.2 Hz), 3.52 (3H, s), 3.75 (2H, t, J=6.2 Hz), 3.71 (3H, s), 6.1
(2H, d and t, J=15.6, 6.2 Hz), 6.3 (1H, d, J=5.6 Hz), 6.4 {1H, s),
6.4 (2H, d, J=15.6 Hz), 6.45 (1H, d, J=5.6 Hz), 7.3 (8H, s), 7.51
(1H, t, J=8.1 Hz), 8.14 (1H, d, J=6.1 Hz), 8.16 (1H, d, J=8.1 Hz),
8.2 (1H, dd, J=1.0, 6.1 Hz), 8.45 (1H, d, J=6.1 Hz), 9.3 (1H, d,
J=1.0 Hz). As described above, the following compounds were
prepared.
EXAMPLE 217
N-[2-4-Methoxy-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
.2HCl
Colorless amorphous form.
IR(KBr)cm.sup.-1 : 3420, 3200-2300, 1720, 1605, 1345, 1280;
UMR(D.sub.2 O) .delta. ppm: 1.59 (3H, d, J=6.71 Hz), 3.19 (2H,
brt.), 3.38 (2H, brt), 4.01 (3H.s), 4.16 (1H, m), 6.28 (1H, dd,
J=15.9, 8.9 Hz), 6.83 (1H, d, J=15.9 Hz), 7.51 (2H, d, J=8.4 Hz),
7.94 (2H, d, J=8.4 Hz), 8.10 (1H, brt), 8.64 (1H, d, J=8.6 Hz),
8.76 (2H, brt), 8.98 (1H, d, J=7.0 Hz), 9.72 (1H, s).
EXAMPLE 218
N-[2-(4-Methoxycarbonyl-N,.alpha.-Dimethylcinnamylamino)Ethyl]-5-Isoquinoli
nesulfonamide.2HCl
Colorless amorphous form.
IR(KBr)cm.sup.-1 : 3420, 3150-2300, 1715, 1605, 1345, 1285;
NMR(D.sub.2 O).delta. ppm=1.59 (3H, .alpha., J=6.4 Hz), 2.94 (3H,
s), 3.44 (4H, brs), 3.99 (3H, s), 4.31 (1H, m), 6.37 (1H, dd,
J=16.2, 8.7 Hz), 6.89 (1H, d, J=16.2 Hz), 7.54 (2H, d, J=8.1 Hz),
8.08 (2H, d, J=8.1 Hz), 8.10 (1H, brt), 8.67 (1H, d, J=8.5 Hz),
8,75 (2H, brt), 8.96 (1H, d, J=7.0 Hz), 9.74 (1H, s).
EXAMPLE 219
N-[2-(4-Methoxy-N,.alpha.-Dimethylcinnamylamino)Ethyl]-5-Isoquinolinesulfon
amide
Colorless oil.
NMR (CDCl.sub.3).delta. ppm: 1.07 (3H, d, J=6.6 Hz), 1.85 (3H, s),
2.3-2.5 (2H, m), 2.91 (2H, t, J=6.0 Hz), 2.95-3.10 (1H, m), 3.80
(3H, s), 5.86 (1H, dd, J=6.0 Hz), 2.95-3.10 (1H, m), 3.80 (3H, s),
5.86 ((1H, dd, J=16.1, 7.3 Hz), 6.24 (1H, d, J=16.1 Hz), 6.84 (2H,
d, J=8.8 Hz), 7.24 (2H, d, J=8.8 Hz), 7.68 (1H, dd, J=7.3, 8.0 Hz),
8.20 (1H, .alpha., J=8.0 Hz), 8.4-8.5 (2H, m), 8.66 (1H, d, J=6.1
Hz), 9.34 (1H, s).
EXAMPLE 220
N-(2-Methylaminoethyl)-N-[2
-(4-Chloro-N-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless oil.
NMR (CDO.sub.3).delta. ppm: 1.9-2.2 (1H, br), 2.23 (3H, s), (3H,
s), 2.59 (2H, t. J=6.6 Hz), 2.80 (2H, t, J=6.1 Hz), 3.12 (2H,
.alpha., J=6.6 Hz), 3.4-5.5 (4H, m), 6.10 ((1H, dt, J=15.9, 6.6
Hz), 6.44 ((1H, d, J=15.9 Hz), 7.26 (4H, s), 7.66 (1H, t, J=15.9,
6.6 Hz), 6.44 (1H, d, J=15.9 Hz), 7.26 (4H, s), 7.66 (1H, t, J=7.8
Hz), 8.17 (1H, d, J=7.8 Hz), 8.40 (1H, d, J=7.8 Hz), 8.46 (1H, d,
J=6.1 Hz), 8.67 (1H, d, J=6.1 Hz), 9.32 (1 H, s).
EXAMPLE 221
N-(2-Methylaminoethyl)-N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl]-5-Isoqui
nolinesulfonamide.3HCl
Colorless amorphous form.
NMR(D.sub.2 O).delta. ppm: 2.80 (3H, s), 3.05 (3H, s), 3.4-3.6 (4H
m) 3.9-4.1 (6H 6.17 (1H, d.t, J=15.9, 7.2 Hz), 6.74 (1H, d, J=15.9
Hz), 7.18 (4H, s), 8.10 (1H, t, J=7.9 Hz), 8.53 (1H, d, J=7.9 Hz),
8.6-8.8 (2H, m), 8.93 (1H, d, J=7.0 Hz), 9.77 (1H, s).
EXAMPLE 222
N-(2-Hydroxyethyl)-N-[2-(4-Methoxy-N,.alpha.-Dimethylcinnamylamino)Ethyl]-5
-Isoquinolinesulfonamide
Colorless amorphous form.
NMR(CDCl.sub.3).delta. ppm: 1.29 (3H, d, J=6.6 Hz), 2.30 (3H, s),
2.7-3.0 (2H, m), 3.2-3.4(5H, m), 3.80 (3H, s), 3.8-3.9 (2H, m),
6.04 (1H, dd, J=16.1, 7.8 Hz), 6.40 (1H, d, J=16.1 Hz), 6.86 (2H,
d, J=16.1, 7.8 Hz), 6.40 (1H, d, J=16.1 Hz), 6.86 (2H, d, J=8.7
Hz), 7.32 (2H, d, J=8.7 Hz), 7.32 (2H, d, J=8.7 Hz), 7.68 (1H, dd,
J=8.0, 7.3 Hz), 8.19 (1H, d, J=8.0 Hz), 8.26 (1h, d, J=7.3 Hz),
8.58 (1H, d, J=6.1 Hz), 8.68 (1H, d, J=6.1 Hz), 8.68 (1H, d, J=6.1
Hz), 9.33 (1H, s).
EXAMPLE 223
N-[2-(Methoxy)Ethyl]-N-[2-(N-Methyl-4-Methoxy-.alpha.-Methylcinnamylamino)E
thyl]-5-Isoquinolinenulfonamide
Colorless oil
NMR(CDCl.sub.3).delta. ppm: 1.12 (3H, d. J=6.6 Hz), 2.18 (3H, s),
2.4-2.65 (2H, m), 3.1 (3H, s), 3.10-3.20 (1H, m), 3.35-3.60 (6H,
m), 3.81 (3H, s), 5.93 (1H, d,d, J=16.1, 7.3 Hz), 6.31 (1H, d,
J=16.1 Hz), 6.85 (2H, d, J=8.7 Hz), 7.62 (1H, dd, J=7.6, 8.1 Hz),
8.13 (1H, d, J=8.1 Hz), 8.35-8.45 (2H, m) 8.67 (1H, d, J=6.1 Hz),
9.30 (1H, s).
EXAMPLE 224
N-[2-(4-Chlorocinnamylamino)Ethyl]-N-(2-Dimethylaminoethyl-5-Isoquinolinesu
lfornamide.3HCl
Colorless amorphous form.
IR(KBr)cm.sup.-1 : 3420, 2700, 1340, 1150, 840, 590
NMR(D.sub.2 O).delta. ppm: 2.99 (6H, s), 3.33 (2H, t, J=6.8 Hz),
3.55 (2H, t, J=6.8 Hz), 3.8-4.0 (6H, m), 6.18 (1H, dt, J=16.2, 6.7
Hz), 6.76 (1H, d, J=16.2 Hz), 7.32 (4H, s), 8.12 (1H, t, J=8.0 Hz),
8.6-8.8(3H, m), 8.97 (1H, d, J=7.0 Hz), 9.74 (1H, s).
EXAMPLE 225
N-[2-(4-Chlorocinnamylamino)ethyl]-N-(2-Methylaminoethyl)-5-Isoquinolinesul
fonamide
Colorless amorphos form.
NMR(D.sub.2 O).delta. ppm: 3.26 (2H, brt), 3.92 (4H, brt), 5.04
(2H, s), 6.1-6.3 (1H, m), 6.77 (1H, d, J=15.6 Hz), 7.38 (4H, s),
7.68 (1H, t, J=6.7 Hz), 8.0-8.3 (2H, m), 8.57 (1H, d, J=5.8 Hz),
8.7-8.9 (3H, m), 9.02 (1H, d, J=7.3 Hz), 9.80 (1H, s).
EXAMPLE 226
N-2-(4-Chlorocinnamylamino)ethyl]-N-(2-Pyridiylmethyl)-5-Isoquinolinesulfon
amide.3HCl
Pale yellow amorphous form.
IR(KBr)cm.sup.-1 : 3420, 2800, 1350, 1150, 590;
NMR(D.sub.2 O).delta. ppm: 3.12 (2H, brt), 3.8-4.0 (4H, m), 4.96
(2H, s), 6.0-6.2 (1H, m), 6.70 (1H, d, J=15.7 Hz), 7.37 (4H, brq),
7.93 (1H, t, J=6.3 Hz), 8.16 (2H, brt), 8.54 (1H, d, J=5.8 Hz),
8.61 (1H, d, J=8.5 Hz), 8.7-8.8 (2H, m), 8.83 (1H, s), 9.01 (1H, d,
J=6.7 Hz), 9.76 (1H, s).
EXAMPLE 227
N-[2-(4-Chlorocinnamylamino)Ethyl]-N-(3-Pyridylmethyl)-5-Isoquinolinesulfon
amide.3HCl
Pale yellow amorphous form.
IR(KBr)cm.sup.-1 : 3420, 2800, 1350, 1150, 590;
NMR(D.sub.2 O).delta. ppm: 3.12 (2H, brt), 3.8-4.0 (4H, m), 4.96.
(2H, s), 6.0-6.2 (1H, m), 6.70 (1H, d, J=15.7 Hz), 7.37 (4H, brq),
7.93 (1H, t, J=6.3 Hz), 8.16 (2H, brt), 8.54 (1H, d, J=5.8 Hz),
8.61 (1H, d, J=6.7 Hz), 9.76 (1H, s).
EXAMPLE 228
N-[2-(3,
4-Dimethoxy-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide.2
HCl
Yellow amorphous form.
HMR(D.sub.2 O).delta. ppm: 1.56 (3H, d, J=6.7 Hz), 3.1-3.2 (2H, m),
3.35-3.45 (2H, m), 3.84 (3H, s), 3.91 (3H, s), 4.0-4.5 (1H, m), 6.0
(1H, dd, J=15.6, 9.0 Hz), 6.64 (1H, d, J=15.6 Hz), 6.92 (3H, s),
8.07 (1H, t, J=8.0 Hz), 8.60 (1H, d, J=8.0 Hz), 8.73 (1H, d, J=8.0
Hz), 8.73 (1H, d, J=6.7 Hz), 8.95 (1H, d, J=6.7 Hz), 9.68 (1H,
s).
EXAMPLE 229
N-[2-(.alpha.-Methyl-3, 4,
5,Trimethoxycinnamylamino)Ethyl]-5-Isoquinolinesulfonamide.2HCl
NMR (D.sub.2 O) .delta. ppm: 1.65 (3H, d, J=6.4 Hz), 3.2-3.5 (4H,
m), 3.84 (3H, s), 3.91 (6H, s), 4.1-4.3 (1H, m), 6.13 (1H, dd,
J=14.1, 8.8 Hz), 6.70 (1H, d, J=14.1 Hz), 6.67 (2H, s), 8.16 (1H,
t, J=8.0 Hz), 8.17 (1H, d, J=8.0 Hz), 8.75-8.85 (2H, m), 9.02 (1H,
t, J=8.0 Hz), 8.17 (1H, d, J=8.0 Hz), 8.75-8.85 (2H, m), 9.02 (1H,
d, J=7.0 Hz), 9.80 (1H, s).
EXAMPLE 230
N-(2-Dimethylaminoethyl)-N-[2-(N-Methyl-3, 4,
5-Trimethoxycinnamylamino)Ethyl]-5-Isonolinesulfonamide
Colorless oil.
NMR(CDCL.sub.3) .delta. ppm: 2.12 (6H, s), 2.22 (3H, s), 2.39 (2H,
t, J=6.8 Hz), 3.10 (2H, d, J=6.6 Hz), 3.4-3.5 (4H, m), 3.84 (3H,
s), 3.87 (6H, s), 6.06 (1H, dt, J=16, 6.6 Hz), 6.40 (1H, d, J=16
Hz), 6.61 (2H, s), 7.64 (1H, t, J=7.4 Hz), 8.15 (1H, d, J=7.4 Hz),
8.44 (2H, m), 8.68 (1H, d, J=6.1 Hz), 9.32 (1H, s).
EXAMPLE 231
N-(2-Dimethylaminoethyl)-N-[2-(N-Methyl-3, 4,
5-Trimethoxycinnamylamino)Ethyl]-5-Isoquinolinesulfonamide.3HCl
Yellow amorphous form.
NMR (D.sub.2 O) .delta. ppm: 3.00 (6H, s), 3.08 (3H, s), 3.80 (3H,
s), 3.82 (6H, s), 3.5-4.1 (10H, m), 6.1 (1H, m), (.2H, s), 6.68
(1H, d, J=16 Hz), 8.0 (1H, t, J=16 Hz), 8.5 (2H, m), 8.7 (2H, m),
9.55 (1H, s).
EXAMPLE 232
N-[2-(4-Chlorocinnamylamino)Ethyl]-N-(3, 4,
5-Trimethoxybenzyl)-5-Isoquinolinesulfonamide.2HCl
Colorless amorphous form.
IR (KBr)cm.sup.-1 =3420, 2920, 1330, 1130, 590;
NMR (DMSO-d.sub.6) .delta. ppm: 2.99 (2H, brs), 3.55 (6H, s), 3.56
(3H, s), 3.68 (4H, brs), 4.47 (2H, s), 6.2-6.4 (1H, m), 6.76 (1H,
d, J=15.9 Hz), 7.45 (4H, s), 7.95 (1H, t, J=7.9 Hz), 8.54 (1H, d,
J=7.6 Hz), 8.6-8.7 (2H, m), 8.78 (1H, d, J=6.3 Hz), 9.48 (2H, brs),
9.73 (1H, s).
EXAMPLE 233
N-Cyanomethyl-N-[2-(4-Methyoxycorbonyl-N-.alpha.-/Dimethylcinnamylamino)Eth
yl]- 5-Isoquinolinesulfonamide
Colorless oil.
IR (KBr)cm.sup.-1 : 2250, 1718, 1280;
NMR (CDCl.sub.3) .delta. ppm =1.16 (3H, d, J=6.6 Hz), 2.23 (3H, s),
2.65-2.8 (2H, m), 3.35 (1H, m), 3.43 (2H, t, J=5.6 Hz), 3.91 (3H,
s), 4.63 (2H, s), 6.23 (1H, dd, J=15.9, 7.1 Hz), 6.46 (1H, d,
J=15.9 Hz), 7.39 (2H, d, J=8.3 Hz), 7.73 (1H, t, J=8.3 Hz), 7.98
(2H, d, J=8.3 Hz), 8.25 (1H, d, J=8.3 Hz), 8.4-8.5 (2H, m), 8.70
(1H, d, J=6.1 Hz), 9.36 (1H, s).
EXAMPLE 234
N-Cyanomethyl-N-[2-(4-Methoxycarbonyl-N,.alpha.-Dimethylcinnamylamino)Ethyl
]-5-Isoquinolinesulfonamide.2HCl
Colorless amouphous form
IRC (KBr)cm.sup.-1 =1718, 1280;
NMR (CDCl.sub.3).delta. ppm: 1.14 (3H, d, J=6.6 Hz), 2.10 (6H, s),
2,21 (3H, s), 2.37 (2H, t, J=7.3 Hz), 2.45-2.65 (2H, m), 3.22 (1H,
m), 3.35-3.50 (4H, m), 3.91 (3H, s), 6.21 (1H, dd, J=1.59, 6.8 Hz),
6.42 (1H, d, J=15.9 Hz), 8.15 (1H, t, J=7.7 Hz), 8.7-8.85 (3H, m),
8.99 (1H, d, J=7.0 Hz), 9.76 (1H, s).
EXAMPLE 235
N-(2-Dimethylaminoethyl)-N-[2-(4-Methoxycarbonyl-N,.alpha.-Dimethylcinnamyl
amino)Ethyl]-5-Isoquinolinesulfonamide
Colorless oil.
IRC (KBr)cm.sup.-1 : 1718, 1280;
NMR (CDCl.sub.3).delta. ppm: 1.14 (3H, d, J=6.6 Hz), 2.10 (6H, s),
2.21 (3H, s), 2.37 (2H, t, J=7.3 Hz), 2.45-2.65 (2h, m), 3.22 (1H,
m), 3.35-3.50 (4H, m), 3.91 (3H, s), 6.21 (1H, dd, J=1.59, 6.8 Hz),
6.42 (1H, d, J=15.9 Hz), 8.15 (1H, t, J=7.7 Hz), 8.7-8.85 (3H, m),
8.99 (1H, d, J=7.0 Hz), 9.76 (1H, s).
EXAMPLE 235
N-(2-Dimethylaminoethyl)-N-[2-(4-Methoxycarbonyl-N,.alpha.-Dimethylcinnamyl
amino)Ethyl]-5-Isoquinolinesulfonamide
Colorless oil.
IRC (KBr)cm.sup.-1 : 1718, 1280;
NMR (CDCl.sub.3).delta. ppm: 1.14 (3H, d, J=6.6 Hz), 2.10 (6H, s),
2.21 (3H, s), 2.37 (2H, t, J=7.3 Hz), 2.45-2.65 (2h, m), 3.22 (1H,
m), 3.35-3.50 (4H, m), 3.91 (3H, s), 6.21 (1H, dd, J=15.9, 6.8 Hz),
6.42 (1H, d, J=15.9 Hz), 7.38 (2H, d, J=8.3 Hz), 7.63 (1H, t, J=7.9
Hz), 7.98 (2H, d, J=8.3 Hz), 8.14 (1H, d, J=7.9 Hz), 8.4-8.5 (2H,
m), 8.67 (1H, d, J=6.4 Hz), 9.31 (1H, s).
EXAMPLE 236
N-(2-Dimethylaminoethyl)-N-[2-(4-Methoxycarbonyl-N,
.alpha.-Dimethylcinnamylamino)-Ethyl]-5-Isoquinolinesulfonamide.3HCl
Colorless amorphous.
NMR (D.sub.2 O).delta. ppm: 1.53 (3H, d, J=6.7 Hz), 2.95 (9H, s),
3.3-3.6 (4H, m), 3.9-4.0 (4H, m), 4.0 (3H, s), 4.25 (1H, m), 6.30
(1H, m), 6.75 (1H, d, J=16.0 Hz), 7.37 (2H, brs), 7.81 (2H, brs),
8.04 (1H, t, J=8.1 Hz), 8.55 (2H, m), 8.65 (1H, d, J=7.0 Hz), 9.60
(1H, s).
EXAMPLE 237
N-(2-Morpholinoethyl)-N-[2-(4-Methoxy-Corbonyl-N,
.alpha.-Dimethylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless oil.
IR (KBr)cm.sup.-1 : 1720, 1280;
NMR (CDCl.sub.3).delta. ppm: 1.15 (3H, d, J=6.4 Hz), 2.21 (3H, s),
2.25-2.7 (2H, m), 3.1-3.3 (1H, m), 3.4-3.6 (8H, m), 3.91 (3H, s),
6.20 (1H, dd, J=16.1, 7.3 Hz), 6.42 (1H, d, J=16.1 Hz), 7.38 (2H,
d, J=8.3 Hz), 7.63 (1H, t, J=7.8 Hz), 8.42 (1H, d, J=7.8 Hz), 8.42
(1H, d, J=7.1 Hz), 8.67 (1H, d, J=7.1 Hz), 9.32 (1H, s).
EXAMPLE 238
N-(2-Morpholinoethyl)-N-[2-(4-Methoxycarbonyl-N,.alpha.-Dimethylcinnamylami
no)ethyl-5-Isoquino-Linesulfonamide.3HCl
Colorless amorphous form
NMR (D.sub.2 O).delta. ppm: 1.55 (3H, d, J=6.8 Hz), 3.00 (3H, s),
3.2-3.7 (8H, m), 3.8-4.1 (8H, m), 4.0 (3H, s), 4.24 (1H, m), 6.35
(1H, m), 6.76 (1H, d, J=16 Hz), 7.40 (2H, brs), 7.82 (2H, brs),
8.06 (1H, t, J=7.5 Hz), 8.5-8.75 (3H, m), 8.80 (1H, d, J=7.0 Hz),
9.63 (1H, s).
EXAMPLE 239
N-(2-Aminoethyl)-N-[2-(4-Methoxycarbonyl-N,
.alpha.-Dimethylcinnamylamino)ethyl]-5 -Isoquinolinesulfonamide
Colorless oil.
IR (KBr)cm.sup.-1 : 1718, 1280;
NMR (CDCl.sub.3).delta. ppm: 1.13 (3H, d, J=6.6 Hz), 2.19 (3H, s),
2.6 (2H, m), 2.86 (2H, brs), 3.22 (1H, m), 3.37 (4H, t, J=6.9 Hz),
3.91 (3H, s), 6.20 (1H, dd, J=16.0, 6.9 Hz), 6.42 (1H, d, J=16.0
Hz), 7.39 (2H, d, J=8.3 Hz), 8.14 (1H, d, J=8.1 Hz), 8.38 (1H, d,
J=8.1 Hz), 8.45 (1H, d, J=6.1 Hz), 8.68 (1H, d, J=6.1 Hz), 9.31
(1H, s).
EXAMPLE 240
N-(2-Aminoethyl)-N-[2-(4-Methoxycarbonyl-N,.alpha.-Dimethylcinnamylamino)Et
hyl]-5-Isoquinolinesulfonamide.3HCl
Colorless amorphous form.
NMR(D.sub.2 O).delta. ppm: 1.53 (3H, d, J=6.4 Hz), 2.96 (3H, s),
3.3-3.5 (4H, m), 3.8-4.0 (4H, m), 4.0 (3H, s), 4.2 (1H, m), 6.3
(1H, m), 6.76 (1H, d, J=15.9 Hz), 7.35 (2H, d, J=8.0 Hz), 7.78 (2H,
brs), 803 (1H, t, J=7.9 Hz), 8.6 (2H, m), 8.66 (1H, d, J=6.7 Hz),
8.85
EXAMPLE 241
N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl]-N-Methoxycarbonylmethyl-5-Isoqu
inoline-Sulfonamide.2HCl
Yellow amorphous form.
IR (KBr)cm.sup.-1 : 3420, 2650, 1750, 1350, 1150, 840, 590;
NMR (D.sub.2 O).delta. ppm: 3.05 (3H, s), 3.51 (2H, brs), 3.61 (3H,
s), 3.89 (2H, brs), 4.06 (2H, d, J=7.3 Hz), 4.45 (2H, s), 6.2-6.4
(1H, m), 6.85 (1H, d, J=15.6 Hz), 34 (4H, brq), 8.12 (1H, t, J=8.0
Hz), 8.6-8.8 (3H, m), 8.95 (1H, d, J=7.0 Hz), 9.79 (1H, s).
EXAMPLE 242
N-Carboxymethyl-N-(2-(4-Chloro-N-Methylcinamylamino)Ethyl]-5-Isoquinolinesu
lfornamide
Pale brown amorpous form.
IR (KBr)cm.sup.-1 : 3420, 1620, 1330, 1140, 590:
NMR(DMSO-d6).delta. ppm: 2.43(3H, s), 2.89 (2H, brt), 3.3-3.6 (4H,
m), 3.91 (2H, s), 6.2-6.4(1H, m), 6.67 (1H, d, J=15.8 Hz), 7.45
(4H, brq), 7.85 (1H, t, J=8.0), 8.3-8.5 (3H, m), 8.71 (1H, d, J=6.2
Hz), 9.49 (1H, s).
EXAMPLE 243
N-[2-(N-Carboxymethyl-4-Chloracinnamylamino)ethyl]-N-Methyl-5-Isoquinoliesu
lfonamide
Pale yellow amorphous form.
IR (KBr)cm.sup.-1 : 3400, 1630, 1320, 1140, 590;
NMR (DMSO-d6).delta. ppm: 2.75 (2H, brt), 2.79 (3H, s), 3.2-3.4(6H,
m), 6.1-6.3 (1H, m), 6.50(1H, d, J=16.2 Hz), 7.39 (4H, brq), 7.83
(1H, t, J=7.8 Hz), 8.3-8.5 (3H, m), 8.68 (1H, d, J=6.1 Hz), 9.48
(1H, s).
EXAMPLE 244
N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl-N-Methyl-5-Isoquinolinesulfonami
de.2HCl
Pale brown amorphous form.
IR (KBr)cm.sup.-1 : 3420, 2670, 1350, 1140, 830, 590;
NMR(D.sub.2 O).delta. ppm: 3.00 (3H, s), 3.04 (3H, s), 3.51 (2H,
brs), 3.66 (2H, brs), 4.10 (2H, brd), 6.2-6.4 (1H, m), 6.90 (1H, d,
J=15.9 Hz), 7.39 (4H, brq), 8.15 (1H, t, J=8.0 Hz), 8.6-8.8 (3H,
m), 9.08 (1H, d, J=6.3 Hz), 9.80 (1H, s).
EXAMPLE 245
N-Carbamoyl-N-[2-(4-Chrolo-N-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfo
namide.2HCl
Colorless amorphous.
IR (KBr)cm.sup.-1 : 3420, 2670, 1680, 1350, 1150, 840, 590;
NMR (D.sub.2 O).delta. ppm: 3.04 (3H, s), 3.4-3.7 (2H, m), 3.89 L-
(2H, brt), 4.06 (2H, brt), 4.29 (2H, s), 6.2-6.4 (1H, 6.86 (1H, d,
J=7.0 Hz), 9.80 (1H, s).
EXAMPLE 246
N-[2-(4-Chlorocinnamylamino)Ethyl]-N-[(5-Methyl-4-Imidazolyl)Methyl]-5-Isoq
uinolinesulfonamide.HCl
Pale yellow amorphous form.
IR (KBr) cm.sup.-1 : 3420, 3020, 1350, 1150, 830, 590;
NMR(D.sub.2 O) .delta. ppm: 2.49 (3H, s), 3.52 (4H, brs), 4.10 (2H,
brd), 4.70 (2H, s), 6.1-6.3 (1H, m), 6.83 (1H, d, J=15.8 Hz), 7.34
(4H, s), 8.10 (1H, d, J=8.0 Hz), 8.6-8.8 (3H, m), 8.83 (1H, s),
8.95 (1H, d, J=7.0 Hz), 9.81 (1H, s).
EXAMPLE 247
N-[2-(4-Chloro-N-Methoxycarbonylmethylcinnamylamino)Ethyl]-N-Methyl-5-Isoqu
nilinesulfonamide.2HCl
Yellow amorphous form.
IR (KBr)cm.sup.-1 : 3420, 2620, 1750, 1350, 1140, 840, 590;
NMR(D.sub.2 O).delta. ppm: 3.07 (3H, s), 3.73 (4H, brt), 3.89 (3H,
s), 4.2 (2H, brd), 4.37 (2H, s), 6.2-6.4 (1H, m), 6.89 (1H, d,
J=16.0 Hz), 7.32 (4H, brq), 8.14 (1H, t, J=7.9 Hz), 8.6-8.8 (3H,
m), 9.04 (1H, d, J=7.0 Hz), (1H, s).
EXAMPLE 248
N-[2-(N-Carbamoylmethyl-4-Chlorocinnamylamino)-ethyl]-N-Methyl-5-Isoquinoli
ne-sulfonamide.2HCl
Pale yellow amorphous form
IR (KBr) cm.sup.-1 : 3400, 1690, 1350, 1140, 830, 590;
NMR (D.sub.2 O) .delta. ppm: 3.05 (3H, s), 3.5-3.8 (4H, m), 4.1-4.2
(2H, m), 4.23 (2H, s), 6.2-6.4 (1H, m), 6.91 (1H, d, J=15.9 Hz),
734 (4H, brq), 8.11 (1H, t, J=7.0 Hz), 8.6-8.8 (3H, m), 9.00 (1H,
d, J=7.0 Hz), 9.80 (1H, s).
EXAMPLE 249
N-[2-(4-Chloro-N-Cyanomethylcinnamylamino)Ethyl)-N-Methyl-5-Isoquinolinesul
fonamide.2HCl
Pale brown amorphous form.
IR (KBr)cm.sup.-1 : 3420, 2570, 1350, 1140, 830, 590;
NMR (DMSO-d6).delta. ppm: 2.80 (2H, brt) 2.89 (3H s) 3.3-3.5 (4H,
m), 3.89 (2H, s), 6.1-6.3 (1H, m), 6.64 (1H, d, J=15.8 Hz), 7.43
(4H, brq), 8.09 (1H, t, J=8.0 Hz), 8.63 (1H, d, J=7.6 Hz), 8.7-8.9
(3H, m), 9.98 (1H, s).
EXAMPLE 250
N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl]-N-Morpholinocarbonylmethyl-5-Is
oquinolinesulfonamide
Colorless oil.
IR (KBr)cm.sup.-1 : 1660, 1330, 1130;
NMR (D.sub.2 O).delta. ppm: 2.17 (3H, s), 2.57 (2H, t, J=6.3 Hz),
3.06 (2H, d, J=6.3 Hz), 3.39 (4H, brs), 3.5-3.7 (6H, m), 4.41 (2H,
s), 6.06 (1H, dt, J=15.9, 6.3 Hz), 6.40 (1H, d, J=15.9 Hz), 7.27
(4H, s), 7.66 (1H, t, J=8.0 Hz), 8.15 (1H, d. J=8.3 Hz), 8.43 (1H,
d, J=6.4 Hz), 8.54 (1H, d, J=8.0 Hz), 8.66 (1H, d, J=6.4 Hz), 9.30
(1H, s).
EXAMPLE 251
N-{2-N-(2-Aminoethyl)-4-Chlorocinnamylamino]Ehtyl}-N-Methyl-5-Isoquinolines
ulfonamide.3HCl
Colorless amorphous form.
IR (KBr)cm.sup.-1 : 3420, 2950, 1490, 1350, 1140, 590;
NMR (D.sub.2 O).delta. ppm: 3.05 (3H, s) 3.5-3.8 (8H, m), 4.20 (2H,
brd), 6.2-6.4 (1H, m), 6.05 (1H, d, J=15.9 Hz), 7 (4H, brq), 8.16
(1H, t, J=7.9 Hz), 8.6-8.8 (3H, m), 9.07 (1H, d, J=7.0 Hz), 9.84
(1H, s).
EXAMPLE 252
N-[2-(4-Chloro-N-Methylcinnamylamino)ethyl]-N-[2-(1-Pyperazinyl)Ethyl]-5-Is
oquinolinesul-Fonamide.4HCl
Colorless amorphous form.
IR (KBr)cm.sup.-1 : 3420, 2660, 1460, 1350, 1150, 590;
NMR (D.sub.2 O).delta. ppm: 3.04 (3H, s), 3.3-3.7 (12H, m), 3.8-4.1
(6H, m), 6.0-6.2 (1H, m), 6.73 (1H, d, J=15.9 Hz), 7.18 (4H, s),
8.11 (1H, t, J=7.9 Hz), 8.53 (1H, d, J=7.3 Hz), 8.6-8.8 (2H, m),
8.89 (1H, d, J=6.9 Hz), 9.78 (1H, s).
EXAMPLE 253
N-[2-(4-Chloro-N-Methylcinnamylamino)Ethyl]-N-[2-(4-Methyl-1-Pyperazinyl)Et
hyl-5 -Isoquinolinesulfonamide.4HCl
Colorless amorphous form
IR (KBr)cm.sup.-1 : 3420, 2660, 1460, 1140, 590;
NMR (D.sub.2 O).delta. ppm: 3.02 (3H, s), 3.3-3.7 (12H, m),
3.8-4.1(6H, m), 6.1-6.3 (1H, m), 6.74 (1H, d, J=16.0 Hz), 7.19 (4H,
s), 8.11 (1H, t, J=7.9 Hz), 8.55 (1H, d, J=7.0 Hz), 8.6-8.8 (2H,
m), 8.90 (1H, d, J=7.0 Hz), 9.79 (1H, s).
EXAMPLE 254
N-[2-(3-Methyoxy-.alpha.-Methylcinnamylamino)ethyl]-5-Isoquinolinesulfonami
de.2HCl
Pale yellow crystalls.
Melting point 115.degree.-118.degree. C.;
IR (KBr)cm.sup.-1 : 3420, 3200-2600, 1605, 1350, 1162, 1150;
NMR (DMSO-d6).delta. ppm: 1.40 (3H, d, J=6.4 Hz), 2.90-3.0 (2H, m),
3.15-3.25 (2H, m), 3.78 (3H, s), 3.80-4.0 (1H, m), 6.22 (1H, dd,
J=15.9, 8.8 Hz), 6.70 (1H, d, J=15.9 Hz), 6.85-7.05 (3H, m), 7.30
(1H, t, J=7.9 Hz), 7.30 (1H, br, disappears in D.sub.2 O), 8.0 (1H,
d, J=7.9 Hz), 8.04 (1H, d, J=7.3 Hz), 8.59 (1H, d, J=7.3 Hz), 8.68
(1H, d, J=7.9 Hz), 8.82 (2H, s), 8.91 (1H, m, disappears in D.sub.2
O), 9.60 (2H, br, disappears in D.sub.2 O), 9.88 (1H, s).
EXAMPLE 255
N-[
2-(4-Hydroxymethyl-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfon
amide
Colorless crystals.
IR (KBr)cm.sup.-1 : 1620, 1326, 1160, 1139, 831, 761, 598;
NMR(CDCl.sub.3).delta. ppm: 1.07 (3H, d, J=6,35 Hz), near 1.95 (3H,
br), 2.60 (2H, t. J=6.0 Hz), 2.96 (2H, m), 3.05 (1H, m), 4.68 (2H,
s), 5.78 (1H, dd, J=15.87, 7.82 Hz), 6.27 (1H, d, J=8.30 Hz), 7.67
(1H, dd, J=8.30, 7.32 Hz), 8.18 (1H, d, J=8.30 Hz), 8.40 (1H, d,
J=6.11 Hz), 8.44 (1H, d, J=7.32 Hz), 8.61 (1H, d, J=6.11 Hz), 9.32
(1H, s).
EXAMPLE 256
N-[2-(.alpha.-Methyl-4-Methylthiocinnamylamino)Ethyl-5-Isoquinolinesulfonam
ide
Colorless amorphous form.
IR (KBr)cm.sup.-1 : 1618, 1493, 1324, 1160, 1138, 1094, 830, 807,
760, 598;
NMR (CDCl.sub.3).delta. ppm: 105 (3H, d, J=6.35 Hz), 2.48 (3H, s),
2.60 (2H, m), 2.96 (2H, t, J=6.10 Hz), 3.03 (1H, m), 5.75 (1H, dd,
J=15.87, 7.81 Hz), 6.22 (1H, d, J=15.87 Hz), 7.18 (4H, s), 7.67
(1H, dd, J=8.30, 7.32 Hz), 8.17 (1H, d, J=8.30 Hz), 8.43 (1H, d,
J=6.10 Hz), 8.44 (1H, d, J=7.32 Hz), 8.68 (1H, d, J=6.10 Hz), 9.34
(1H, s). cl EXAMPLE 257
N-[2-(.alpha.-Methyl-4-Methylsulfinylcinnamylamino)Ethyl]-5-Isoquinolinesul
fonamide
Colorless amorphous form.
IR (KBr)cm.sup.-1 : 1618, 1326, 1160, 1138, 1089, 1041, 831, 762,
599;
NMR(CDCl.sub.3).delta. ppm: 1.11 (3H, d, J=6.59 Hz), 2.0-4.0 (2H,
br), 2.65 (2H, m), 2.73 (3H, s), 3.00 (2H, t, J=5.62 Hz), 3.15 (1H,
m), 5.96 (1H, dd, J=16.11, 7.81 Hz), 6.36 (1H, d, J=16.11 Hz), 7.42
(2H, d, J=8.30 Hz), 7.58 (2H, d, J=8.30 HZ), 7.68 (1H, dd, J=8.31,
7.32 Hz), 8.10 (1H, d, J=8.30 Hz), 7.68 (1H, dd, J=8.31, 7.32 Hz),
8.19 (1H, d, J=8.31 Hz), 8.44 (1H, d, J=6.1 Hz), 8.44 (1H, d,
J=7.32 Hz), 8.67 (1H, d, J=6.10 Hz), 9.35 (1H, s).
EXAMPLE 258
N-2-(.alpha.-Methyl-4-Methylsulfonyalcynnamylamino)Ethyl]-5-Isoquinolinesul
fonamide
Colorless amorphous
IR (KBr)cm.sup.-1 : 1310, 1149, 1090, 960, 832, 765, 599, 542;
NMR (CDCl.sub.3).delta. ppm: 1.09 (3H, d, J=6.35 Hz), 2.62 (2H, m),
2.98 (2H, t, J=5.62 Hz), 3.05 (3H, s), 3.10 (1H, m), 6.02 (1H, dd,
J=15.87, 7.57 Hz), 6.37 (1H, d, J=15.87 Hz), 3.05 (3H, s), 3.10
(1H, m), 6.02 (1H, dd, J=15,87, 7,57 Hz), 6.37 (1H, d, J=15.87 Hz),
7.44 (2H, d, J=8.30 Hz), 7.69 (1H, dd, J=8.06, 7.57 Hz), 7.85 (2H,
d, J=8.30 Hz), 8.20 (1H, d, J=8.06 Hz), 8.44 (1H, d, J=6.35 Hz),
8.45 (1H, d, J=7.57 Hz), 8.67 (1H, d, J=6.35 Hz), 9.36 (1H, s).
EXAMPLE 259
N-[2-(4-Cyano-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamide
Colorless needles.
Melting point: 62.degree.-65.degree. C.;
IR (KBr) cm.sup.-1 : 2230, 1620, 1322, 1140, 600;
NMR (CDCl.sub.3).delta. ppm: 1.08 (3H, d, J=6.3 Hz), 2.57-2.65 (2H,
m), 2.9-3.0 (2H, m), 3.0-3.2 (1H, m), 5.98 (1H, dd, J=15.9, 7.8
Hz), 6,33 (1H, d, J=15.9 Hz), 7.36 (2H, d, J=8.3 Hz), 7.58 (2H, d,
J=8.3 Hz), 7.69 (1H, t, J=8.0 Hz), 8.20 (1H, d, J=8.0 Hz),
8.40-8.50 (2H, m), 8.69 (1H, d, J=6.1 Hz), 9.36 (1H, s).
EXAMPLE 260
N-[2-(4-Carbamoyl-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonam
ide
Color less needles
Melting point: 66.degree.-70.degree. C.;
IR (KBr)cm.sup.-1 : 3450, 1662, 1610, 1320, 1160, 1140;
NMR (CDCl.sub.3).delta. ppm; 1.08 (3H, d, J=6.4 HZ), 2.61 (2H, M),
2.90-3.20 (3H, m), 5.93 (1H, dd, J=16.1, 7.8 Hz), 6.32 (1H, d,
J=16.1 Hz), 7.32 (2H, d, J=8.3 Hz), 7.66 (1H, t, J=8.3 Hz), 7.74
(2H, d, J=8.3 Hz), 8.18 (1H, d, J=8.3 Hz), 7.74 (2H, d, J=8.3 Hz),
8.18 (1H, d, J=8.3 Hz), 8.40-8.50 (2H, m), 8.67 (1H, d, J=6.1 Hz),
9.34 (1H, s).
EXAMPLE 261
N-[2-(4-Acetamide-.alpha.-Methylcinnamylamino)ethyl]-5-Isoquinolinesulfonam
ide
Colorless amorphous form.
IR (KBr)cm.sup.-1 : 3300-2800, 1670, 1600, 1538, 1320, 1160,
1140;
NMR (CDCl.sub.3).delta. ppm; 1.03 (3H, d, J=6.6 Hz), 2.16 (3H, s),
2.55-2.65 (2H, m), 2.90-3.10 (3H, m), 5.68 (1H, dd, J=15.9, 8.1
Hz), 6.20 (1H, d, J=15.9 Hz), 7.17 (2H, d, J=8.5 Hz), 7.44 (2H, d,
J=8.5 Hz), 7.66 (1H, dd, J=8.3, 7.3 Hz), 8.44 (1H, d, J=7.3 Hz),
7.66
(1H, s, disappears in D.sub.2 O), 8.16 (1H, d, J=8.3 Hz), 8.44 (1H,
d, J=7.3 Hz), 8.44 (1H, d, J=6.1 Hz), 8.61 (1H, d, J=6.1 Hz), 9.31
(1H, s).
EXAMPLE 262
N-[2-(3-Nitro-3-Methoxy-.alpha.-Methylcinnamylamino)Ethyl]5-Isoquinolinesul
fonamide.HCl
Colorless crystals.
Melting point: 159.degree.-163.degree. C.;
IR (KBr) cm.sup.-1 : 3450, 3150-2600, 1530, 1330, 1160, 1140;
NMR (DMSO-d6).delta. ppm: 1.34 (3H, d, J=6.6 Hz), 2.75-3.0 (2H, m),
3.02-3.20 (2H, m), 3.90 (3H, s), 3.90-4.10 (1H, m), 6.30 (1H, dd,
J=15.6, 8.6 Hz), 6.57 (1H, d, J=15.6 Hz), 7.26 (1H, d, J=7.8 Hz),
7.32 (1H, d, J=7.8 Hz), 7.83 (1H, t, J=7.8 Hz), 8.35-8.45
(3H, m), 8.52 (1H, brs, disappears in D 0), 8.7 (1H, d, J=6.1 Hz),
9.25 (2H, brs, disappears in D.sub.2 O), 9.47 (1H, s).
EXAMPLE 263
N-[2-(2-Methoxy-.alpha.-Methylcinnamylamino)Ethyl]-5-Isoquinolinesulfonamid
e
Colorless amorphous form.
IR (KBr) cm.sup.-1 : 1490, 1463, 1326, 1244, 1160, 1138, 755,
599;
NMR (CDCl.sub.3) .delta. ppm: 1.05 (3H, d, J=6.35 Hz), 2.6 (2H, m),
2.96 (2H, t, J=5.62 Hz), 3.04 (1H, m), 3.82 (3H, s), 5.79 (1H, dd,
J=16.12, 7.94 Hz), 6.85 (1H, brd, J=8.06 Hz), 6.90 (1H, brt, J=7.57
HZ), 7.21 (1H, m), 7.31 (1H, dd, J=16.12, 7.94 Hz), 6.85 (1H, brd,
J=8.06 Hz), 6.90 (1H, brt, J=7.57 Hz), 7.21 (1H, m) 7.31 (1H, dd,
J=7.57, (1.71 Hz), 7.66 (1H, dd, J=8.06, 7.57 Hz), 8.16 (1H, t,
J=8.06 Hz), 8.44 (2H, m), 8.67 (1H, d, J=6.35 Hz), 9.33 (1H,
s).
EXAMPLE 264
To confirm the usefulness of the above-mentioned compound of the
present invention, the following experiments were carried out.
Vessel Smooth Muscle Relaxation Action (V.R. ED.sub.50)
A rabbit was killed by bleeding and the superior mesenteric artery
was removed and cut to a spiral form to prepare a band-shaped
specimen according to a conventional method. The specimen was
suspended by loading a strain in Krebs-Henseleit solution through
which an oxygen gas containing 5% carbon dioxide was bubbled. The
specimen was contracted by adding potassium chloride to maintain a
predetermined strain. Thereafter, a test compound was cumulatively
administrated. The relaxation activity of the test compound was
expressed by ED.sub.50 (.mu.M), i.e., a concentration of the
compound which relaxes the strain to 50% of the strain only in the
presence of potassium chloride (as 100%)
Platelet Acclutination Inhibition (P.A.; IC.sub.50)
(1) Preparation of washed platelets
The blood was obtained from a healthy person and mixed with one
tenth volume of 0.38% sodium citrate, and the mixture was
centrifuged at 700.times.G for 10 minutes to obtain a platelet-rich
plasma (PRP). To the PRP was added one sixth volume of ACD solution
(2.2% sodium citrate, 0.8% citric acid and 2.2% glucose; freshly
prepared before use) and the mixture was centrifuged at
1500.times.G for 10 minutes to obtain a platelet pellet. Next, the
platelet pellet was suspended in a modified HEPES-Tyrode solution
(135 mM NaCl, 2.7 mM KCl, 1 mM MgCl.sub.2, 0.1 mg/ml glucose, 20 mM
HEPES; pH 7.4). To this suspension was added one sixth volume of
ACD solution, and the whole was further centrifuged at 1500.times.G
for 5 minutes to prepare a platelet pellet. The platelet pellet was
then suspended in a modified HEPES Tyrode solution to obtain about
3.times.10.sup.5 /.mu.l in washed platelet suspension.
(2) Measurement of platelet Agglutination
To 270 .mu.l of the washed platelet suspension was added 3 .mu.l of
a solution of a test compound dissolved in an appropriate medium in
different concentration, and the mixture was pre-incubated at
37.degree. C. for 2 minutes. After an addition of 30 .mu.l of 20
.mu.g/ml collagen solution, the absorbance was measured with
4-channel agglutination analyzer (HEMA Tracer 601; Niko
Bioscience).
(3) Determination of effect of test compounds
As a control, the above-mentioned procedure was carried out except
that the test medium without a test compound was used, and the
absorbance before addition of collagen and the maximum absorbance
after addition of collagen were measured, and the difference
between both absorbances was taken as 100% agglutination.
For test compound, the absorbance before an addition of collagen
and the maximum absorbance after an addition of collagen were
measured, and a percent of the inhibition was determined, compared
with the control. A concentration of test compound which provides
50% of the inhibition expressed as IC.sub.50.
Calmodulin-Dependent Phosphodiesterase Inhibition
(1) Preparation of Calmodulin-Dependent
Phosphodiesterase (Ca.sup.2+ PDE)Ca.sup.2+ PDE was partially
purified from the brain of rat by DEAE-Sepharose column
chromatography.
(2) Preparation of calmodulin
Calmodulin was purified from the calf brain using a calmodulin
inhibitor W-7 affinity column.
(3) Measurement of Ca.sup.2+ PDE activity
A reaction mixture contained 20 .mu.l of 500 mM Tris-HCl (pH 8.0),
20 .mu.l of 50 mM MgCl.sub.2, 20 .mu.l of 2 mM CaCl.sub.2 (or 10 mM
EGTA), 20 .mu.l of 1 mg/ml bovine serum albumin, PDE, 200 mg of
calmodulin, test sample and distilled water to make total volume
200 .mu.l. To the mixture was added 20 .mu.l of 4 .mu.M [.sup.3
H]-cGMP (2.5 .mu.Ci/ml), the mixture was incubated at 30.degree. C.
for 15 minutes, and then heated in boiling water for 3 to 5 minutes
to terminate the reaction, and cooled in ice-water bath. 20 .mu.g
of 5'-nucleotidase (Snake venum) was added to the mixture, and the
mixture was again incubated at 30.degree. C. for 10 minutes. After
addition of about 2 ml of water, the sample was applied to a cation
exchange resin column (Biorad AG.AG50W-X4 to adsorbe the [.sup.3
H]-guanosine and additionally about 2 ml of washing water for the
sample was added to the column. The column was washed with about 20
ml of water, and the adsorbed [.sup.3 H]-guanosine was eluted with
3 ml of 3N NH.sub.4 OH, and the elute was directly received by a
vial. After an addition of 10 ml of an emulsified scintillation
solution (ACS-II, AMERSHAM) the radio activity was measured by a
scintillation counter LS7500 (Beckmann). The enzyme activity in the
presence of calmodulin was taken as 0%, and a concentration of a
test compound in .mu.M which provides a 50% inhibition was
expressed as IC.sub.50.
The results are set forth in the following Table.
______________________________________ Example P.A. (IC.sub.50)
Ca.sup.2+ PDE (IC.sub.50) No. V.R. (ED.sub.50) (.mu.M) (.mu.M)
______________________________________ 1 2 47 3 4 12 53 5 6 7 1.6
13 8 1.8 51 9 10 6.4 37 11 59 12 13 1.2 15 14 15 43 16 17 18 19 22
20 20 1 23 21 22 1.8 23 0.25 66 24 8.3 63 25 0.55 70 26 10 27 28 29
7.6 73 30 31 24 .+-. 7.0 32 33 21 34 1.8 35 6.9 36 0.81 10.5 37 4.4
29 38 8.1 39 40 4.7 41 1.8 10 42 6.2 43 0.36 3.8 44 45 7.5 46 4 36
47 0.39 18 48 3.9 6.5 49 0.92 50 0.67 70 11 51 0.17 38 52 9.9 53
1.3 54 1.7 55 8.6 56 1.2 39 57 0.75 50 58 0.25 63 59 60 10 61 10 62
2.3 63 64 65 66 67 2.2 3.6 68 3.3 .+-. 1.4 6 69 14 70 71 14 93 72 4
6.2 73 14 21 74 2.8 75 9.7 76 2.9 77 1.4 78 1.8 79 5.5 80 2.4 13 81
1.7 32 82 0.86 33 83 0.39 24 84 43 85 75 86 13 24 87 1.7 1.9 88 4.3
14 89 90 0.33 3.4 91 1.1 10 92 63 93 0.31 3.4 94 95 96 97 39 98 22
99 2.8 61 100 95 101 29 102 24 103 104 105 5.4 12 106 8.9 28 107
108 1.2 10 109 0.59 1.3 110 3.8 9.3 111 7.0 77 112 113 0.88 20 1.2
114 54 100 115 116 1.5 117 118 119 11 51 120 19 .+-. 3.0 121 122
123 4.8 22 124 11 125 9.2 126 10 127 39 128 1.8 129 0.82 130 13 131
1.5 132 133 134 135 136 137 138 139 140 141 142 6.8 1.1 143 0.82 15
144 1.8 1.0 145 12 146 2.8 147 1.2 42 148 149 150 151 152 153 1.5
25 154 60 155 4.1 55 156 4.4 19 19 157 3.2 36 8.6 158 17 21 159 5.1
24 92 160 1.8 56 161 4.7 162 35 163 31 164 4.1 165 11 166 1.4 90
167 1.2 52 168 3.6 26 169 4.6 170 5.2 171 5.4 172 1.0 51 9.4 173
174 11 175 2.0 13 176 1.2 55 8.5 177 2.7 56 24 178 2.4 50 179 2.8
51 7.8 180 1.8 4.8 181 8.4 38 4.7 182 17 183 2.8 184 2.8 12 185
0.21 186 187 188 4 189-I 0.22 2.7 189-II 0.20 189-III 0.29 1.0 190
0.19 191 1.9 26 192 0.12 84 193 3.2 12 194 80 195 196 197 198 199
200 201 3.2 202 1.3 203 204 205 206 207 208 209 210 211 212 213 214
215 216 ______________________________________
It was shown that other compounds of the present inventions
described above have a platelet agglutination-inhibitory action as
well as an inhibitory action against protein kinase A, myosin light
chain kinase, protein kinase C, calmodulin-dependent protein kinase
II, cyclic AMP dependent phosphodiesterase and the like, but have
little effect on cardiac functions.
As seen from the above-mentioned results, the present compound a as
described above have a smooth muscle relaxation action, and
therefore, are useful as vasodilator or brain circulation-improving
agents; and since the present compound have a platelet
agglutination-inhibitory action, they are useful as prophylactic or
therapeutic agents for thrombosis Moreover, since the present
compounds have an inhibitory activity against various kinases, they
are useful as anti-tumor agents. The above-mentioned compounds have
a low toxicity, and therefore, are applicable as pharmaceutical
preparations.
* * * * *